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CHAPTER 3
Appendageal Tumours
Appendageal tumours are neoplasms whose differentiation is toward one or more of the adnexal structures of the skin. While mesenchymal tumours of various kinds are technically in this category, conventionally, the term refers to those with origin from, or differentiation toward epithelial adnexal neoplasms. Depending on their presumed origin, adnexal tumours are categorized into those with apocrine and eccrine, foliicular and sebaceous differentiation. For most of these tumour types there are benign and malignant counterparts. The histopathologicalcriteria for prognosis of biological behaviour are well established. The WHO Working Group was aware of recent evidence indicating that basal cell carcinoma (BCC) should be included under the adnexal neoplasms under the term trichoblastic carcinoma. The inclusion of BCC in the chapter on keratinocytic tumours reflects the traditional categorization but does not indicate that the Working Group denies their adnexal origin.
WHO histological classification of appendageal tumours

Tumours with apocrine and eccrine differentiation Malignant tumours Tubular carcinoma Microcystic adnexal carcinoma Porocarcinoma Spiradenocarcinoma Malignant mixed tumour Hidradenocarcinoma Mucinous carcinoma Digital papillary carcinoma Adenoid cystic carcinoma Apocrine carcinoma Paget disease of breast Extramammary Paget disease Benign tumours Hidrocystoma Syringoma Poroma Syringofibroadenoma Hidradenoma Spiradenoma Cylindroma Tubular adenoma Tubular papillary adenoma Syringocystadenoma papilliferum Hidradenoma papilliferum Mixed tumour (chondroid syringoma) Tumours with follicular differentiation Malignant tumours Pilomatrical carcinoma Proliferating tricholemmal tumour Benign tumours Trichoblastoma Pilomatricoma Tricholemmoma Multiple tricholemmomas Trichofolliculoma Fibrofolliculoma / trichodiscoma Tumours with sebaceous differentiation Sebaceous carcinoma Sebaceous adenoma Sebaceoma Cystic sebaceous tumour 8211/0 8263/0 8406/0 8405/0 8940/0
8211/3 8407/3 8409/3 8403/3 8940/3 8400/3 8480/3 8408/3 8200/3 8401/3 8540/3 8542/3
8110/3 8103/1 8100/0 8110/0 8102/0 8102/0 8101/0 8391/0
8404/0 8407/0 8409/0 8392/0 8402/0 8403/0 8200/0
8410/3 8410/0 8410/0 8410/0
__________ 1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
TNM classification of skin appendageal carcinomas

TNM classification 1,2 T Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ T1 T2 Tumour 2 cm or less in greatest dimension Tumour more than 2 cm but no more than 5 cm in greatest dimension T3 Tumour more than 5 cm in greatest dimension T4 Tumour invades deep extradermal structures, i.e., cartilage, skeletal muscle, or bone Note: In the case of multiple simultaneous tumours, the tumour with the highest T category is classified and the number of separate tumours is indicated in parentheses, e.g., T2(5). N Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis
__________ 1 {894,2219}. 2 A help desk for specific questions about the TNM classification is available at www.uicc.org/index.php?id=508 .
M Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis
Stage grouping Stage 0 Tis Stage I T1 Stage II T2, T3 Stage III T4 Any T Stage IV Any T
N0 N0 N0 N0 N1 Any N
M0 M0 M0 M0 M0 M1
122 Appendageal tumours
Appendageal skin tumours: Introduction
P.E. LeBoit
Epidemiology Most studies on adnexal neoplasms have taken place in western countries with Caucasian populations. Benign adnexal neoplasms tend to occur in younger patients than carcinomas do. Adnexal carcinomas vary from those in which actinic damage is the norm, such as the common basal cell carcinoma (which differentiates toward follicular germ) to those that seem to have little relationship to sun exposure (such as spiradenocarcinoma). Etiology No known triggering event is evident in the vast majority of adnexal neoplasms. There are some cases in which the cause is an autosomal dominant mutation in a tumour suppressor gene. Clinical signs and symptoms Most benign adnexal neoplasms are smooth surfaced, symmetrical papules or nodules the same colour as the patients skin or darker. Some, such as sebaceous adenoma and syringocystadenoma papilliferum, have eroded surfaces, but in general, ulceration is a sign of malignancy. Most adnexal carcinomas are irregularly shaped plaques, sometimes ulcerated. Tumour spread and staging In general, low-grade carcinomas seldom metastasize; for some, e.g. microcystic adnexal carcinoma, metastasis has not yet been recorded. A haematogenous pattern seems the rule for a few carcinomas, such as adenoid cystic carcinoma, but most can spread via either lymphatic or haematogenous dissemination. Carcino-mas with eccrine differentiation have a propensity to metastasize to the skin. Sentinel node biopsy While a few sentinel node biopsies have been performed for adnexal carcinomas, not enough data have been collected to validate this procedure {274}.
Pathology Diagnostic criteria of adnexal carcinomas > Irregular borders, asymmetry at scanning magnification > Horizontal orientation > Markedly irrregular aggregates of epithelial cells > Necrosis en masse > Infiltration of the dermis or subcutis without the interposition of densely fibrotic stroma > Mitoses frequent, can be atypical > Stroma irregular, often scant, sometimes myxoid > Nuclei pleomorphic. Some neoplasms with monomorphous nuclei, e.g. microcystic adnexal carcinoma, are exceptions. Diagnostic criteria of benign epithelial adnexal neoplasms {28}: > Symmetric and smooth bordered at scanning magnification > Vertically oriented with respect to the surface of the skin > Aggregates of epithelial cells uniform > No necrosis en masse (with the excetion of poroma) > Mitoses variable, but typical > Densely fibrotic stroma, rich in fibrocytes in the case of trichogenic > Neoplasms forming a blunt, rounded interface with the native dermis. An exception is poroma, which has vascular, myxoid stroma. > Nuclei monomorphous; rare exceptions include atypical squamous nuclei in poromas. Immunoprofile Most adnexal neoplasms are accompanied by variably dense infiltrates of Tcells. These are intimately admixed with the neoplasm (spiradenoma, cutaneous lymphadenoma, adamantinoid trichoblastoma) and lymphoepithelioma-like carcinoma among malignancies are examples. Syringocystadenoma papilliferum has a complement of plasma cells, many of which secrete IgA.
A complex array of keratins are expressed in adnexal neoplasms. Those with follicular germinative differentiation express cytokeratins seen in follicular germs in embryonic and neonatal life. Those with ductular differentiation have lumens that stain for carcinoembryonic antigen (CEA), and express simple epithelial keratins. Sebaceous differentiation is characterized by expression of epithelial membrane antigen in a microvacuolar pattern. Precursor lesions Benign adnexal neoplasms of various sorts can arise in naevus sebaceous, a malformation involving the epidermis, dermis and adnexae. Otherwise, most benign adnexal neoplasms arise de novo. This is also the case for malignant adnexal neoplasms. Rare apocrine carcinomas arise in naevus sebaceous. Rarely, porocarcinoma, spiradenocarcinoma or hidradenocarcinoma may arise in a pre-existent poroma, spiradenoma, or hidradenoma, respectively. The vast majority of basal cell carcinomas arises de novo. Rarely, basal cell carcinomas occur in pre-existent trichoblastomas. Histogenesis The origin of most adnexal neoplasms is unknown. It is better to speak of their differentiation. The most clear-cut evidence of differentiation is in follicular neoplasms, where such signs as follicular papillae and germs (as in the trichoblastomas) or trichohyaline granules (as are focally found in pilomatricoma and in matrical carcinomas) can occur. Clearcut apocrine differentiation, in which decapitation secretion of columnar cells that have brightly eosinophilic cytoplasmic granules is also specific. However, there is a marked similarity between eccrine and apocrine ducts. Also, the columnar cells of eccrine secretory coils can resemble poorly differentiated apocrine secretory cells. Hence, neoplasms with ductular differentiation often have debatable histogenesis {1543}. To some
Introduction 123
extent, the differentiation of neoplasms probably reflects their distribution {1544}. Genetics Approximately one third of sweat gland carcinomas contain TP53 mutations {239A}. Otherwise, little is known about the genetics of most epithelial neoplasms, with the exception of those that occur in multiplicity as part of autosomal dominant syndromes (see Chapter 7). The mutations found in the germlines of patients with syndromes and multiple tumour suppressor genes tend to be the same as occur as somatic mutations in sporadic adnexal neoplasms. Some trichoblastomas have mutations in the PTCH gene, as found in naevoid basal cell carcinoma syndrome (Gorlin-Goltz
syndrome). Trichilemmomas have mutations in PTEN, the same gene as involved in Cowden syndrome. Mutations in DNA repair genes occur in the sebaceous neoplasms of the Muir-Torre syndrome and, to a lesser degree, in sporadic sebaceous neoplasms. Prognosis and predictive factors In general, adnexal carcinomas of low cytologic grade have a good prognosis, especially if the lesion is relatively small and completely excised. Those of high cytologic grade may metastasize widely. For many adnexal carcinomas, there are simply insufficient numbers of reported cases to develop much of an idea regarding their prognosis.
Malignant tumours with apocrine and eccrine differentiation
L. Requena H. Kutzner M. A. Hurt D. J. Santa Cruz A.H. Mehregan
Y. M. Mengesha S. Kohler Z B. Argenyi J. McNiff P. Rudolph O. P. Sangeza
Tubular carcinoma
Definition Tubular carcinoma is the malignant counterpart of tubular adenoma, featuring apocrine differentiation with prominent tubular structures. ICD-O code 8211/3
Historical annotation Probably the first reported examples of tubular carcinoma were included in the series of carcinomas of sweat glands published by Stout and Cooley in 1951 {2274}. Epidemiology Tubular carcinoma seems to be slightly more frequent in women. Most patients are middle-aged adults. Localization The axilla is the most common location, with rare bilateral involvement. Other sites rich in apocrine glands may also be involved {114,127,1705,1785,2274,2397, 2460,2569}. Clinical features Tubular carcinoma usually presents as a firm erythematous nodule, which may be ulcerated or adherent to deeper tissues. Tubular carcinomas may arise in naevus sebaceous {644}.
Histopathology At scanning magnification, the neoplasm is asymmetric, poorly circumscribed, and infiltrative with prominent and crowded tubular and ductal structures. The lesion often involves the full-thickness of the dermis and it may extend to the subcutaneous tissue. Neoplastic structures show marked variation in size and shape, but, in general, the size of the tubules tends to decrease from superficial to deeper areas. The more superficial larger tubules may show luminal papillations. At higher magnification, epithelial cells lining the tubules show abundant eosinophilic or granular cytoplasm and pleomorphic nuclei, some of them in mitosis. Often the cytoplasm of these cells exhibits signs of decapitation secretion. Lumina are often filled with homogenous eosinophilic material, foamy histiocytes and necrotic debris. Examples of tubular carcinoma may also exhibit focally solid areas with a combination of cribriform or adenoid cystic patterns as additional morphologic expressions. Areas of necrosis en masse are also frequent, but in contrast with adenoid cystic carcinoma, tubular carcinoma shows no deposits of basement membrane material within the aggregations of neoplastic cells and perineural involvement is usually absent. The stroma is sparse. Before a diagnosis of primary tubular
carcinoma of the skin is established, the possibility of cutaneous metastasis from a visceral tubular carcinoma should be ruled out. Immunoprofile Tubular carcinoma shows immunoreactivity with low molecular weight cytokeratins and the luminal cells express EMA and GCDFP-15. Expression of CEA is variable {1785,2569}. Histogenesis The presence of decapitation secretion and continuity between neoplastic tubules and follicular infundibula are signs of apocrine differentiation. This is further supported by enzyme histochemistry. Prognosis and predictive factors Tubular carcinoma of the skin behaves in a highly malignant fashion. Of the 44 examples reported in the literature, neoplasms from 21 patients metastasized and at least 9 patients died as a result of widespread metastatic disease {1705, 1785,2397,2569}.
Microcystic adnexal carcinoma

Definition Microcystic adnexal carcinoma {861} is a locally infiltrative and destructive low-
A
Fig. 3.01 Tubular carcinoma on the retroauricular left region.
Fig. 3.02 Tubular carcinoma. A The neoplasm involves the full-thickness of the dermis and extends into subcutaneous tissue. The stroma is sparse and the epithelium predominates over the stroma. B Some neoplastic aggregations of this tubular carcinoma exhibit focally an adenoid cystic pattern.
Malignant tumours with apocrine and eccrine differentiation 125
grade adenocarcinoma differentiated toward ducts. It has little capacity to metastasize. ICD-O code 8407/3
Synonyms Sclerosing sweat duct carcinoma {541}, eccrine epithelioma, syringomatous carcinoma. Clinical features The carcinoma occurs on the face of adults, more commonly in women. It affects commonly the face {469} and lip, uncommonly other locations, and grows slowly over a period of months to years. It is similar usually to a depressed scar and rarely causes ulceration. Histopathology The classical pattern is that of small, superficial, solid to cystic structures that are similar to small infundibular cysts and ducts. In the middle depth, the lesion is composed completely of small ducts, often in very subtle patterns, frequently with involvement of nerves and perineural spaces. In the deepest areas, Indian filing and sclerosis are common findings. Thus, there is a sense that the lesion is stratified from superficial (tubules and
Fig. 3.03 Microcystic adnexal carcinoma. Scanning magnification of microcystic adnexal carcinoma illustrates the zonal effect with solid nests and cysts superficially with complex glands deep.
cysts) to deep (epithelial cords and sclerosis). Unusual examples contain sebocytic zones {1862}, and others contain areas similar to follicular sheath, thus suggesting differentiation toward the folliculosebaceous-apocrine unit. In other cases, the lesions are exclusively ductal, causing some authors to designate them as syringomatous carcinoma or sclerosing sweat duct carcinoma and suggesting that these examples could be derived from eccrine ducts. Some MACs have solid poromatous or clear cell cytol-
ogy. Cytologically, the lesions are well differentiated, lacking nuclear pleomorphism or mitotic figures. In fact, the finding of nuclear pleomorphism should cause one to reconsider whether the diagnosis of microcystic adnexal carcinoma is correct. Immunoprofile There is cytoplasmic staining with AE1/AE3, CK7, and bcl-2. EMA and BerEP4 stain in a membranous pattern around ductal cells near the lumen. Alpha SMA and S100 protein stain the
Fig. 3.04 Microcystic adnexal carcinoma. A There are a few cysts and solid nests, but no nuclear pleomorphism. The pattern of the lesion helps to recognize it as carcinoma. B Not only are there ducts; there are also strands and small nests of neoplastic cells. C This example of microcystic adnexal carcinoma again illustrates the zonation pattern, in this case with a few cysts superficially. Note the deep nests that are present in and around the sucutis; not every case will contain compressed ducts exclusively in the deep zones. D This example is similar to some poromas. There are solid nests of monomorphous cells as wells as nests of cells with clear cytoplasm. Some authors have designated these lesions "syringomatous" carcinoma. E Despite the striking structural patterns of these lesions, most do not contain nuclear pleomorphism. F Peripheral nerve, completely encircled by the neoplasm. Note the ductal space.
tubules peripherally. P53 is positive in less than 25% of the neoplastic cells. There is a low proliferative index, as Ki67 is positive in less than 5% of the neoplastic cells. CK20, c-erb-2, and CD34 are negative {2207}. Differential diagnosis The principal differential diagnoses are with superficial biopsies of columnar trichoblastoma (desmoplastic trichoepithelioma) or morpheiform basal cell carcinoma (trichoblastic carcinoma), all of which are CK7 negative. Syringoma is a possible consideration in some cases. Rare examples of metastatic carcinoma to the skin can also mimic it. Genetics There is a single report of a 6q deletion {2538}. There is also a report of 2 microcystic adnexal carcinomas, one of which was diploid, and the other, aneuploid, when examined with DNA image cytometry {2437}. Prognosis Treatment is surgical, with microscopic control of margins if possible {9}. Radiotherapy has proven successful rarely, but some reported cases have taken on an even more virulent biology after such treatment.
Fig. 3.05 Malignant mixed tumour. Lobulated biphasic tumour consisting of epithelial and mucinous-mesenchymal components. The former predominate at the periphery, while the latter predominate at the center.
A
Malignant mixed tumour
Definition Malignant mixed tumour (MMT) is an exceedingly rare cutaneous adnexal carcinoma with a significant risk for aggressive behaviour and a propensity for metastasis. MMT is regarded as the malignant counterpart of benign mixed tumour {1919} albeit histological diagnosis is foremost based on the biphasic nature of the neoplasm rather than an admixture of benign mixed tumour remnants with carcinomatous tissue {2515}. ICD-O code 8940/3
Synonyms Malignant apocrine mixed tumour. Malignant chondroid syringoma. Epidemiology MMT represents an exceedingly rare cutaneous adnexal neoplasm which occurs in a wide age range (15 months
Fig. 3.06 Malignant mixed tumour. A Hyperchromatic tumour cells with mitoses. B Note variations of cytological differentiation and pleomorphism. C Focal zone of tubule formation. D Highly pleomorphic tumour lobules with mitoses at the periphery of the tumour. E Note the pseudo-sarcomatous pattern with hyperchromatic spindle cells and many mitoses. F Nests of plasmacytoid tumour cells amidst a myxoid stroma. Plasmacytoid epithelial differentiation is a hallmark of myoepithelial differentiation.
to 89 years; average 50 years) and is twice more common in women than in men {177,1919}. Localization In marked contrast to its benign counterpart MMT shows a predilection for the trunk and the extremities, foremost the hands and feet {177,961,1593,1903, 1919,2177,2377}. Clinical features MMT shares most clinical characteristics with its benign counterpart, albeit tumours of the former are much larger at the time of presentation (2-15 cm in diameter). Rarely, rapid growth, ulceration, or pain in a previously indolent skin tumour indicate carcinomatous growth. Most MMT, however, present in a rather bland way with a long history prior to excision. These tumours are well circumscribed and may appear cystic. They are not painful, not ulcerated, and show no distinctive clinical appearance. Macroscopy Grossly, most MMT are firm, circumscribed, asymmetrical cutaneous or subcutaneous tumours with a diameter of up to 15 cm. The tumour cut surface may reveal gelatinous material in variable amount {1919}. Because of the infiltrative tumour growth enucleation is not possible. Histopathology MMT originates within the dermis or superficial subcutis, and presents as a large, asymmetrical, poorly circumscribed, lobulated biphasic tumour with infiltrative tumour margins and adjacent satellite tumour nodules. Juxtaposed areas of benign and malignant mixed tumour may rarely occur, but are not a prerequisite for the diagnosis of MMT. MMT is composed of both epithelial and mesenchymal components, with epithelial components predominating at the periphery and mesenchymal chondromyxoid elements being more abundant toward the centre {2100}. The chondromyxoid tumour stroma is PAS-negative and consists of hyaluronic acid and sulphated acid mucopolysaccharides {1112}. Stroma ossification is rare {961, 2177}. Epithelial tumour aggregations present as confluent cords and nests of variable size and shape, with interspersed zones of tubule formation.
Tubular structures may be either of the elongated apocrine type lined by at least two layers of epithelial cells, with luminal cells exhibiting signs of apocrine secretion and abluminal cells showing plasmacytoid / myoepithelial differentiation, or more rarely of the eccrine type showing small round structures lined by a single layer of atypical epithelial cells {961, 1919}. Often, however, MMT consists only of solid aggregations devoid of tubules {928, 1919, 2471}. Epithelial tumour cells may either have a deceptively bland appearance {1112,2100} or show distinctive atypia and pleomorphism of nuclei with a high nuclear-cytoplasmic ratio and numerous mitotic figures {1919}. Zones of necrosis are common. Characteristic epithelial tumour cells are cuboidal with distinctive polygonal or plasmacytoid features {961, 1919}. The latter is considered an indicator of the myoepithelial/apocrine origin of the neoplasm and may be seen as a clue to the diagnosis of MMT {1919}. Immunoprofile Tumour cells may show a myoepithelial immunophenotype with coexpression of S100 and cytokeratin {177,976,1839, 2471} and actin expression in a minority of cells {1488}. Spindle cells within the myxoid stroma are vimentin-positive {2117}. Electron microscopy Tumour cells exhibit ultrastructural features of myoepithelia with desmosomes and abundant intracytoplasmic filaments {177,1839,2471}. However, ultrastructural studies so far have not presented convincing evidence of either apocrine or eccrine differentiation of MMT {1919}. Variants MMT may exhibit deceptively bland cytological features {1112,2100} albeit associated with distinctive architectural criteria of malignancy, e.g. asymmetry, poor circumscription, infiltrative tumour margins, and satellite nodules. The recently described malignant mixed tumour of soft tissue {1062} shows overlapping histologic criteria with MMT of the skin. The former is considered to be part of the morphological spectrum of myoepithelial tumours of soft tissue. Differential diagnosis Extraskeletal myxoid chondrosarcoma
consists of non-cohesive elongated tumour nests without ductal or tubular structures. Tumour cells are cytokeratin negative. Mucinous carcinoma and myxopapillary ependymoma show distinct PAS positivity of the extracellular myxoid stroma. Cutaneous myoepithelial carcinoma favours monophasic differentiation with a very discrete myxoid stroma {1585}. MMT and cutaneous myoepithelial carcinoma may fall along a spectrum of tumours with overlapping histologic appearances {1585}. Histogenesis MMT probably does not originate in association with its benign counterpart, but develops de novo {1919}. A myoepithelial origin of MMT appears to be most plausible {177,1585,2100}, and MMT may be included in the spectrum of cutaneous myoepithelial neoplasms {1585}. Prognosis and predictive factors MMT proliferates in an invasive and destructive fashion, with a high rate of local recurrences and metastases (>50%) into regional lymph nodes, lung, and bone {177,1593}. Death ensues in >25% {177}. However, in >30% MMT neither recurred nor metastasized (atypical mixed tumour of the skin) {177}. In general, MMT is characterized by its prolonged course {2467}. It is remarkable that non-metastasizing MMTs showed the same histological spectrum as those of proven malignancy {1919}, ranging from bland cytological appearance {961} to marked nuclear pleomorphism and a high mitotic count {2377}. Complete excision before metastasis results in tumour free survival {1919}.
Porocarcinoma
Definition Eccrine porocarcinoma is a malignant tumour related to the sweat gland duct, showing both intraepidermal and dermal components. ICD-O code 8409/3
Synonyms and historical annotation Epidermotropic eccrine carcinoma, malignant eccrine poroma, malignant hidroacanthoma simplex, malignant intraepidermal eccrine poroma, poroepithelioma. The tumour was first described
B
Fig. 3.07 Porocarcinoma. A Multinodular ulcerated plaque. B Closely arranged polygonal cells with hyperchromasia. Fig. 3.08 Porocarcinoma. There is a dermal component, partly in apposition with the epidermis, and a large tumour nodule extending into the deep subcutaneous tissues. The lesion is remarkably well demarkated.
by Pinkus and Mehregan in 1963 as epidermotropic eccrine carcinoma {1837}. Epidemiology Eccrine porocarcinoma is a rare tumour, predominantly observed in elderly patients with an average age of 67 years {1072}. Women and men are equally affected. The incidence in one large series was 18 per 450,000 cases (0.004%) {1571}. Etiology Eccrine porocarcinomas may arise de novo or as a malignant transformation in a pre-existing poroma, hidroacanthoma simplex, or in association with naevus sebaceous {1571,2216,2604}. 18 to 50% of eccrine porocarcinomas are associated with pre-existing eccrine poromas. Localization Forty-four to 50% of eccrine porocarcinomas arise on the legs, buttocks, or feet {2216}. The trunk accounts for 24% of the lesions and the head 18% of the lesions with less frequent lesions located on the upper extremities {1072}. Clinical features Eccrine porocarcinoma presents as a verrucous nodulo-ulcerative plaque. Clinically the lesions may resemble an eccrine poroma, verruca vulgaris, seborrhoeic keratosis, melanocytic naevus,
fibroma, basal cell carcinoma, squamous cell carcinoma, or pyogenic granuloma. Diagnosis is made by skin biopsy. Histopathology Eccrine porocarcinoma forms intraepidermal and dermal nests and cords of epithelial cells with pale cytoplasm. The tumour masses form clearly demarcated and frequently rounded nests of polygonal cells with pleomorphic and irregularly-shaped nuclei, prominent nucleoli, and numerous mitotic figures. There is sharp demarcation of the epithelial nests of cells from the adjacent epidermal keratinocytes {1837}. The overlying epidermis may be acanthotic. Both single tumour cells and nests of cells may involve the epidermis in a pagetoid fashion {1359}. Keratinization is usually absent. Intercellular bridging between the tumour cells is inconspicuous. The tumour cells may contain glycogen {2000}. Connection to the intradermal eccrine ducts may be observed. Deep dermal intralymphatic invasion may be observed in up to 15% of the lesions {1952}. The differential diagnosis includes eccrine poroma, hidroacanthoma simplex, and Paget disease {913}. Eccrine poroma and hidroacanthoma simplex may show focal atypia, but the lesions are symmetrical and well circumscribed. Eccrine porocarcinoma may be differen-
tiated from Paget disease by its relatively sparse epidermal involvement and greater dermal invasion, and the presence of glycogen rather than mucin in tumour cells {913}. In the absence of residual eccrine poroma, it is very difficult to differentiate eccrine porocarcinoma from squamous cell carcinoma {1571}. Immunoprofile The tumour nodules stain with antibodies to pan-cytokeratin; tumour cells may stain paler than adjacent epidermal keratinocytes {499,1072}. Ductal structures within the tumour stain strongly positive with CEA and EMA {1359,2216}. Genetics Mutation of the p53 gene with loss of its suppressor function has been widely noted with malignant transformation. P53 protein expression has been observed in both eccrine poromas and eccrine porocarcinoma {43,2327}. P16 staining is uniformly negative {914}. Prognosis and predictive factors Approximately 20% of eccrine porocarcinomas recur after excision {2216}. Regional lymph node metastasis occurs in 20% of patients, while 12% develop distant metastases {2216}. Patients with metastatic disease have a high mortality rate {170}. Increased number of mitoses,
Fig. 3.09 Spiradenocarcinoma. A Transitional changes from benign to malignant. Note transitional area with hypercellularity, hyperchromasia and diminished preservation of the usual histologic pattern of a spiradenoma. B Spiradenocarcinoma with transitional changes from benign to malignant. Malignant area with occasional residual duct-like structures with clear cell changes and prominent cytologic atypia. C Spiradenocarcinoma with unusual cytodifferentiation, squamous "bowenoid" dysplasia.
lymphovascular invasion and tumour depth greater than 7 mm have all been associated with a relatively poor prognosis {1952}.
Synonym Malignant spiradenoma Epidemiology Spiradenocarcinoma is an extremely rare tumour. Approximately 50 well-documented cases have been reported. The tumour mainly affects middle age persons (mean age is 55 yr), and its incidence is similar in both sexes. Localization Spiradenocarcinoma can affect any body site, but the most common locations are the upper extremities, followed by the lower extremities, trunk, and the head and neck areas {725,884}. Clinical features Typically there is a history of a longstanding lesion that suddenly became enlarged, ulcerated, tender, or changed its colour. The size of the tumour ranges from 0.8-10 cm. The mean duration of a pre-existent lesion is about 20 years before the diagnosis is made {725}. The patient may also have multiple longstanding spiradenomas, which often coexist with cylindromas {89}.
Histopathology In all cases there are recognizable areas of a benign spiradenoma with the usual well-defined dermal nodules composed of two cell types. Spiradenocarcinoma arising from benign spiradenoma presents two major histologic patterns {89, 725,884}. In one type, there are areas showing gradual transition from benign to a malignant neoplasm. In these lesions the dual cell population of the benign neoplasm imperceptibly merges with the monomorphous cell population of the carcinoma. The usual structural pattern of spiradenoma disappears and is replaced by poorly defined cell nests and cords. Glandular and duct-like structures, as well as hyaline globules, are diminished or may be missing. These changes can be very focal in early lesions and can easily be missed without adequate tissue sampling. In the second type, the malignant changes are adjacent to the spiradenoma without structural or cytological transition. These neoplasms can present a wide spectrum of histologic features including squamous, bowenoid, adenomatous, ductal carcinoma-like, and even histiocyte-like and carcinosarcomatous changes with rhabdomyoblastic or osteosarcomatous differentiation {1391,1548,1958}. In advanced stages of both subtypes, necrosis, haemorrhage, and infiltrative growth can be observed. Immunoprofile Spiradenocarcinoma is positive for the majority of cytokeratins, CEA, EMA, and shows a spotty reaction for S-100 protein. Over-expression of P53 has also been reported {89,726,1555,2516}.
Spiradenocarcinoma
Definition Spiradenocarcinoma is a malignant adnexal neoplasm resulting from malignant transformation of a benign spiradenoma. ICD-O code 8403/3
Fig. 3.10 Spiradenocarcinoma. Well-defined, encapsulated mass with areas of solid and cystic changes and haemorrhage.
Fig. 3.11 Hidradenocarcinoma involving the left preauricular skin of an elderly male. Note the presence of a retroauricular lymphadenopathy.
Fig. 3.12 Hidradenocarcinoma. A At scanning power the neoplasm appears as a well-circumscribed round nodule involving the full thickness of the dermis. B Although the neoplasm is mostly a solid tumour, in some areas there is evidence of ductal differentiation in the form of cytoplasmic vacuoles and small round ducts.
Histogenesis Theoretically, spiradenocarcinoma can develop de novo. However, the tumour lacks distinctive microscopic features, therefore its histopathologic diagnosis requires recognition of a spiradenoma in association with the malignant changes. Somatic genetics TP53 mutations have been identified in carcinomatous portion of spiradenocarcinoma, whereas the spiradenoma part lacked mutations {239A}. Prognosis and predictive factors Spiradenocarcinoma is an aggressive neoplasm with multiple local recurrences and eventual widespread metastases, resulting in death. The metastases most often involve lymph nodes, bones, and lungs. Management is primarily surgical; the role of radiation and chemotherapy is still to be defined {1110,1594}.
moid hidradenocarcinoma {637}, and malignant nodular clear-cell hidradenoma {204}. Epidemiology Hidradenocarcinoma seems to be slightly more frequent in women than in men, with the mean age of 50 years, but cases have been also recorded in children {237,477}. Etiology Most cases of this carcinoma arise de novo, but some cases are associated with a hidradenoma {237,1013,1237, 1249,1427}. Localization This carcinoma may appear in any area. Clinical features The neoplasm does not have any distinctive clinical features and usually presents as a slow growing solitary dermal or subcutaneous nodule. Histopathology Hidradenocarcinoma is composed of one or several tumour nodules, which vary in size and shape. Focal tubular and ductal structures may be present. Areas of necrosis en masse are common. Usually there is no connection between the epidermis and the tumour, but the surface epithelium may be ulcerated. The same cell types as seen in hidradenoma are found in hidradenocarcinoma. Atypical cells with pleomorphic nuclei and mitotic figures may be focally prominent, but some tumours lack nuclear atypia. Therefore, the diagnosis can be established only on the basis of architectural characteristics.
Immunoprofile Neoplastic cells express low molecular weight cytokeratin CAM 5.2 and cytokeratin 19. CEA and EMA decorate the luminal border of ductal structures. Histogenesis Most neoplasms have apocrine differentiation, but some show eccrine features. Prognosis and predictive factors This carcinoma may metastasize widely and cause death. Of the 76 patients with this carcinoma described in the literature, 22 developed metastases {204,485, 992,1013,1162, 2468}.
Hidradenocarcinoma
Definition Hidradenocarcinoma is the malignant counterpart of hidradenoma. ICD-O code 8400/3
Synonyms Clear-cell papillary carcinoma {1436}, clear-cell hidradenocarcinoma {1249, 1470}, malignant clear-cell hidradenoma {578,1237}, malignant clear-cell acrospiroma {992}, malignant eccrine acrospiroma {1741}, primary mucoepidermoid carcinoma of the skin {803, 2497}, nodular hidradenocarcinoma, clear-cell eccrine carcinoma {2300}, mucoepider-
Fig. 3.13 Mucinous carcinoma. Note typical "honeycomb pattern" with small epithelial strands floating in lakes of mucin.
Fig. 3.14 Mucinous carcinoma. A Large mucin deposits clearly predominate over epithelial tumour components - in sharp contrast to cutaneous metastasis of mucinous breast carcinoma where epithelial tumour cells predominate and delicate fibrous septa are scarce. B Thin strands of epithelial tumour cells with little atypia and very scarce mitoses. Note delicate fibrous septa and incipient tubule formation.
Mucinous carcinoma
Definition Primary cutaneous mucinous carcinoma (MC) is a rare epithelial neoplasm occurring mostly, but not exclusively, in middle-aged and older patients. Although MC is characterized by destructive local growth and the potential of metastasizing to regional lymph nodes and even beyond them, it generally follows an indolent course with frequent local recurrences. Mucinous carcinoma metastatic to skin from another organ, particularly the breast and gastrointestinal tract, may be histologically indistinguishable from MC. ICD-O code 8480/3
ing, painless nodular neoplasm. The tumour has a tan, grey, or reddish colour, a smooth surface, and a consistency ranging from soft to firm. Positive transillumination may be a helpful diagnostic tool. Macroscopy Grossly, most MC are well-circumscribed, un-encapsulated tumours in the dermis and the subcutaneous fat. Tumour diameters range between 1 and 8 centimetres, albeit larger variants have been reported {1231}. On excision, the tumour appears fixed to the adjacent dermis and does not shell out {1919}. The cut surface of excised specimens is gelatinous. Histopathology MC presents as an un-encapsulated asymmetric dermal tumour that may extend into the subcutis and even deeper tissue planes {1919}. Tumour satellites may occur at some distance from the main tumour. MC is characterized by large pools of basophilic mucin, which are compartmentalized by delicate fibrous septa, thereby creating a honeycomb pattern. Within the lakes of mucin are small floating islands and bizarre clusters of neoplastic epithelial cells, sometimes exhibiting a cribriform arrangement. The epithelial component is denser at the periphery of the tumour. Small glandular or tubular structures containing mucin or showing signs of apocrine secretion occur only rarely. The small neoplastic cells are cuboidal, round, or oval with abundant cytoplasm
that may be vacuolated. Nuclei are small with very little atypia. Mitoses are rare. The epithelial mucin is PAS-positive, hyaluronidase and sialinase labile, and consists of non-sulphated acid mucopolysaccharides with sialic acid. Immunoprofile Neoplastic cells express low molecular weight cytokeratins, CEA, EMA, GCDFP15, alpha-lactalbumin, salivary amylase, beta-2-microglobulin. S100 expression is inconstant {199,404,664}. Nuclear expression of oestrogen receptors may be strong, but the pattern of progesteron receptors is more variable {945}. Cytokeratin 20 expression allows differentiation of mucinous gastrointestinal carcinoma metastatic to the skin from primary cytokeratin 20-negative cutaneous MC {664}. Variants MC very rarely presents with focal neuroendocrine differentiation {1876}, or with a growth pattern imitating infiltrating carcinoma of the breast {2557}. Epidermotropism of neoplastic cells is unusual. Electron microscopy There are less well-differentiated inner pale cells and mucin-containing peripheral dark cells {990}. Differential diagnosis Before a diagnosis of MC is established, a primary carcinoma in a breast or another organ (salivary and lacrimal glands, gastrointestinal tract, nose and
Synonyms Primary cutaneous mucinous carcinoma. Colloid, gelatinous and adenocystic carcinoma. Epidemiology MC is very rare and occurs mostly between the fifth and seventh decades of life, with an age range between 8 and 84 years. MC is slightly more common in men than in women {1919}. Localization Most MC arise on the head, favouring scalp and face with preference of the eyelids {199,305,1212,2217,2319}. Rare sites are axillae, trunk, lower extremities, perianal area and vulva {1919}. Clinical features MC presents as a solitary, slowly grow-
paranasal sinuses, bronchi, ovary and renal pelvis) should be specifically sought and excluded as most cases of mucinous carcinoma in the skin are metastatic to it. Histological differentiation between primary cutaneous MC and metastatic mucinous carcinoma to the skin may be impossible, albeit the latter exhibits subtle histological variations {1919}: e.g. larger clusters of cohesive neoplastic cells, less quantities of mucin, a striking predominance of epithelium over mucin, and the absence of delicate fibrous septa that intersect the lakes of mucin. Malignant mixed tumour of the skin exhibits tubular structures embedded in a myxoid, chondroid, or osteoid stroma, and distinctive polygonal and plasmacytoid neoplastic epithelia. The characteristic honeycomb pattern of MC is not present {1919}. Histogenesis Histogenesis of MC has not yet been elucidated, but there is strong morphological evidence that MC may be apocrine in nature {1919}. Prognosis and predictive factors In contrast to most other sweat gland carcinomas, MC is a low-grade malignant neoplasm with a tendency to persist at the original site but with a low metastatic potential. 10% of the MC so far reported metastasized to regional lymph nodes, but only 3% metastasized in a more widespread fashion {1830}. While multiple recurrences, due to the existence of tumour satellites, are not unusual, death from MC is exceptional {1919}.
Fig. 3.15 Digital papillary carcinoma. Within the tumour nodules, papillae are formed by heaped up epithelium without stromal cores.
cases originally classified histologically as adenoma developed metastases, demonstrating that histologic parameters do not accurately predict behaviour or allow distinction between adenoma and adenocarcinoma {655}. Therefore, the term aggressive digital papillary adenoma has been abandoned in favour of classification of all such lesions as digital papillary carcinoma. Epidemiology Digital papillary carcinomas present almost exclusively on the fingers, toes, palms, and soles. Hands are involved more frequently than feet. There is a male predilection, and most affected individuals are adults in the fifth and sixth decades of life. Clinical features Most cases present as a slowly growing deeply seated nodule on a digit. Lesions may be several centimetres in diameter. Pain is occasionally a presenting complaint, and may be related to tumour extension into underlying bone, joint, or nerve. Rarely, metastasis is the first manifestation of disease. Unless underlying bone has been invaded, routine roentgenographic examination may be essentially unremarkable. Histopathology Typically, tumours are composed of multi-nodular epithelial aggregates with cystic spaces in the dermis. A cribriform
pattern of glands often fills the solid areas of tumour, while papillary epithelial projections are common within cystic spaces. The papillary projections are associated with fibrovascular cores in some areas, while in other areas papillae are formed by heaped up epithelium without stromal support. The epithelium is composed of low columnar or cuboidal cells. Cytologic atypia is usually not marked. Mitoses and necrosis are frequent findings. Cysts contain either necrotic debris or eosinophilic secretory material. Some tumours are well-circumscribed, while others have an infiltrative growth pattern. Differential diagnosis The differential diagnosis includes papillary eccrine adenoma, which is usually well-circumscribed, and composed of dilated ducts with a distinct two cell layer and delicate papillae. Malignant adnexal neoplasms such as malignant acrospiroma and malignant spiradenoma are also in the differential, but typically lack the pattern of papillary growth and/or backto-back glands that characterize digital papillary carcinoma. In addition, malignant spiradenoma usually retains its characteristic two cell population (small basaloid cells and large pale peripheral cells) in at least some foci. Histogenesis The occurrence of digital papillary carcinoma on acral sites where eccrine
Digital papillary carcinoma

Definition Digital papillary carcinoma is regarded as an uncommon malignant adnexal neoplasm with potential for both recurrence and metastasis. ICD-O code 8408/3
Synonyms Aggressive digital papillary adenoma, digital papillary adenocarcinoma Historically, this group of lesions was divided histologically into aggressive digital papillary adenomas and digital adenocarcinomas {1205}. However,
glands are abundant suggests an eccrine origin of this tumour. Although some cases show decapitation secretion, as is common in apocrine lesions, this phenomenon has also been observed in eccrine tumours. In addition, immunoreactivity for ferritin had led investigators to favour that digital papillary carcinomas derive from eccrine glands {417}. Prognosis and predictive factors Complete surgical excision with negative margins is indicated, and sometimes requires amputation. Tumour recurrence is seen in up to 50% of patients, especially in cases without adequate primary excision {1205}. Metastatic disease has been observed in 14% of cases {655}. Metastases may accompany recurrent disease or occur without evidence of local recurrence. Lungs seem a favoured site for metastases, suggesting the probability of haematogenous spread of tumour. Tumour recurrence and metastasis does not seem to correlate with patient age, tumour size, or duration of tumour. Similarly, histologic features such as tumour differentiation, circumscription, or nuclear grade are not predictive of behaviour {655}.
Adenoid cystic carcinoma

Definition Primary cutaneous adenoid cystic carcinoma is a neoplasm of disputed histogenesis characterized by a cribriform pattern and frequent perineural involvement. ICD-O code 8200/3
Fig. 3.16 Adenoid cystic carcinoma. A Low power view of an adenoid cystic carcinoma demonstrating a poorly circumscribed neoplasm which is composed of collections of basophilic cells arranged in a sievelike pattern. B This photograph highlights the sieve-like pattern with prominent mucin within the glandular spaces. Note also the irregularity of the size and shape of the cellular collections. C Mild degree of pleomorphism is seen within the neoplastic cells.
Epidemiology Over 40 cases have been reported in the literature. Adenoid cystic carcinoma (ACC) affects middle-aged and older individuals (mean age: 58.1) and has a predilection for women {1219}. Localization This neoplasm is most common on the scalp (35%) and chest and abdomen (24%) {446,1219}. Clinical features Primary cutaneous adenoid cystic carcinoma has an indolent and progressive course. The average duration of the tumour prior to diagnosis is approximate-
ly 9.8 years {1219}. The size of the tumour ranges from 0.5-8 cm, with an average size of 3.2 cm. Patients typically present with slowly expanding, firm, skin coloured nodules. Tenderness, ulceration and bleeding are variable and depend on the site of involvement. In the scalp region, alopecia may be an associated finding. Histopathology Primary cutaneous ACC is usually poorly circumscribed and is composed of islands, cords and strands of basaloid cells with a glandular, cystic, cribriform and tubular arrangement embedded in a loose fibrous and sometimes mucinous stroma. It typically occupies the mid and deep dermis and may extend into the subcutaneous fat {793}. The epithelial cords have an infiltrative pattern and are not connected to the overlying epidermis. The tumour has a characteristic basophilic appearance on low power
due to nuclear hyperchromatism and crowding. Nuclear palisading is absent. The tumour nests are surrounded by a prominent eosinophilic hyaline basement membrane-like material which is periodic acid-Schiff-positive, and diastase-resistant. The cystic spaces often contain abundant mucin {1812}. The mucin is characteristically alcian blue (pH 2.5) positive. The epithelium consists of fairly uniform cells with darkly staining nuclei, which sometimes contain conspicuous, small, solitary nucleoli. Individual tumour cells have a scant amphophilic cytoplasm and an increased nuclear-cytoplasmic ratio. Mitotic activity is usually sparse with 1-2 division figures per high power field (x40) {2514}. Perineural extension, a characteristic feature of salivary gland adenoid cystic carcinoma may be seen, however, not with the frequency seen in other organs. Before the diagnosis of a primary cutaneous ACC is made, the possibility of a
metastasis from other organs needs to be ruled out on clinico-pathological grounds. The adenoid cystic type of basal cell carcinoma is differentiated by the presence of palisading of the nuclei and stromal retraction. Immunoprofile Primary cutaneous adenoid cystic carcinoma stain positively for epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), broad-spectrum keratins, and low-molecular-weight keratins (CAM 5.2). Focal staining with S-100 and vimentin may be seen {210}. Epithelial cells at the periphery of the tumour islands may express actin. Histogenesis The eccrine or apocrine origin of this tumour remains disputed. In the past, it has been regarded as an eccrine tumour, although some have been shown to arise from modified apocrine glands {2407}. Prognosis and predictive factors An indolent but progressive course is the major characteristic of this tumour. The recurrence rate is high, ranging from 5770% and therefore wide surgical excision extending well beyond the clinical confines of the tumour is recommended. Recurrences have been reported even with 2 cm margins and may occur many years after excision. For this reason some people favour Mohs micrographic surgery {462}. Only 4 cases have metastasized to the lymph nodes and lungs.
Apocrine carcinoma
Definition Apocrine carcinoma (AC) is a malignant sweat gland neoplasm with apocrine differentiation. Although an apocrine origin has also been postulated for adenoid cystic carcinoma, hidradenocarcinoma, spiradenocarcinoma, malignant cylindroma, and microcystic adnexal carcinoma, this remains unproven. These entities shall, therefore, be presented separately. ICD-O code 8401/3
gland carcinoma) and the eyelid (Moll gland carcinoma) {2139,2172}. Clinical features Because reports are sporadic and may have included a proportion of benign lesions it is difficult to establish a precise clinical profile for AC. Apparently, there are no distinctive features that might enable a confident clinical diagnosis of AC. Most tumours are solitary, but a patient with bilatelal axillary AC has been reported. AC presents as single or multiple, firm or cystic nodules with a reddish or purplish hue of the ovelying skin, sizing between 1.5 and 8 cm {2460}. Ulceration and haemorrhage may be present. The patients age at presentation ranges from 25 to 91 years, with an average age of 57.9 years {2460}. In many cases, the lesions had been standing for more than 10 years, and even up to 30 years before diagnosis {1650}. Some tumours have arisen within a naevus sebaceous {644}. Histopathology AC is typically centred on the deeper dermis and tends to spread into the subcutaneous fatty tissue {1785,2460}. Extension into the epidermis also occurs, occasionally in the form of extramammary Paget disease {1647}. The tumours are usually poorly circumscribed with infiltrating borders. Neighbouring apocrine glands occasionally show in situ carcinoma. {988,2460}. The growth patterns of AC are highly variable, including tubular,
Synonyms Apocrine adenocarcinoma, apocrine gland carcinoma Epidemiology AC is a rare tumour. Both genders are almost equally affected, and there appears to be no racial predilection. {1785,2460} Etiology The etiology of AC is unknown. The fact that all patients were over 25 years {824} suggests that full maturity of the apocrine glands is a prerequisite. Localization Most AC arise in the axilla and, to a lesser extent, in the anogenital region. Rare locations include the scalp, face, chest, and distal upper extremities. {536,988, 1785,2055,2460} Peculiar variants have been described on the ear (ceruminous
Fig. 3.17 Apocrine carcinoma. A Well differentiated cutaneous apocrine carcinoma. Glandular structures with tubulopapillary growth pattern and apical decapitation secretion. B Poorly differentiated cutaneous apocrine carcinoma. Micronodular and trabecular growth pattern with hardly any gland formation, hyaline stroma. The cells have scanty amphophilic cytoplasm and contain vesicular nuclei with prominent nucleoli and occasional mitotic figures.
papillary, cystic, cribriform, micronodular, and solid formations {1785,2460}. The cells have abundant eosinophilic cytoplasm and large, round to oval, mostly vesicular nuclei that often contain a single prominent eosinophilic nucleolus {1785}. Intacytoplasmic PAS-positive diastase-resistant granules are characteristic, and intracytoplasmic iron is sometimes demonstrable {988,1785,2139}. A key diagnostic criterion, decapitation secretion in the form of apical snouts {2460} is usually recognizable but may be lacking in poorly differentiated tumours. There is variable mitotic activity, ranging from single mitotic figures in well differentiated tumours and up to 4 mitotic figures per high power field in poorly differentiated carcinomas {2460}. Long standing tumours tend to show increasing anaplasia. The tumour stroma is usually densely fibroblastic or hyaline and may contain prominent lymphoplasmacytic infiltrates. AC may exhibit focal mucinous carcinoma-like features {2556} or may be composed of signet ring cells {1126}. The latter tumours are mostly located on the eyelid but may occur in the axilla {1343}. Signet ring cell AC show a striking predominance (10:1) in elderly males {1343}. Immunoprofile The cells of AC express low molecular weight cytokeratin (CAM5.2), epithelial membrane antigen, carcinoembryonic antigen, cytokeratin15, gross cystic disease fluid protein (GCDFP)-15 {1785} and occasionally S-100 protein {1343, 1785}. Myoepithelial cells, detectable by SMA or CK 5/6 immunostaining, are typically absent {988,2460}. Differential diagnosis The main differential diagnosis is with (tubular) apocrine adenoma, and the histologic features that distiguish these two conditions are often subtle. Whilst vascular and neural invasion are diagnostic of carcinoma, stromal invasion is less so and may be difficult to ascertain. Tumour silhouette, cellular pleomorphism and mitotic activity may provide clues to malignancy. As focal squamous differentiation may occur in AC {1785} acantholytic squamous cell carcinoma may have to be considered in the diagnostic differential. AC is otherwise indistinguishable from apocrine mammary carcinoma metastat-
Fig. 3.18 Mammary Paget disease (MPD). Sharply circumscribed erythematous and scaly plaque affecting the nipple and areola.
Fig. 3.19 MPD. Cytoplasmic melanin can accumulate in Paget cells and does not indicate melanocytic differentiation.
ic to the skin or apocrine carcinomas arising in ectopic breast tissue in the axilla. Therefore, the diagnosis of primary cutaneous AC rests on a meticulous clinico-pathologic correlation. Histogenesis AC is thought to arise from preexisting apocrine (sweat) glands {988,1785,2139, 2459}. An interesting alternative origin are the newly described mammary-like sweat glands of the anogenital region, which may also give rise to eccrine tumours {2408}. Prognosis and predictive factors The majority of AC are slow growing tumours with a tendency toward a prolonged course. The overall mortality is low, despite frequent recurrences (30%) and metastases to regional lymph nodes (50%) {536,1785,2460}. Wide dissemination and tumour-related deaths have nevertheless been described {437,1785, 2172,2460}. As distant metastases may be a late event in the course of AC a prolonged follow-up is advisable. Reliable predictive factors have not been established.
underlying in situ or invasive ductal carcinoma of the breast. Extramammary Paget disease (EMP) is a scaly erythematous eruption affecting apocrine gland bearing areas of the skin, mainly the female and male genital areas. The majority of cases represent an apocrine adenocarcinoma in situ that has a high recurrence rate and may invade the dermis and then possesses metastatic potential. In a subset of cases EMP is the skin manifestation of an underlying internal malignancy. The skin manifestations of these cases are clinically and histologically indistinguishable from cases not associated with internal malignancy. ICD-O codes Paget disease of breast 8540/3 Extramammary Paget disease 8542/3 Historical annotation In 1874 Sir James Paget first described about fifteen cases of a chronic eczematous eruption of the nipple and areola and noted that mammary cancer developed in all patients within two years {1766}. George Thin described the histopathologic features of this condition in 1881. The term Paget disease was coined in 1889 by Radcliffe Crocker when he described a morphologically and histologically similar eruption affecting the penis and scrotum {561}. Epidemiology MPD occurs almost exclusively in women. Exceptional cases of men with MPD have been reported {927}. One to two percent of female patients with breast carcinoma develop Paget disease {1971}. Ten to 28% of cases of Paget dis-
Paget disease and extramammary Paget disease

Definition Paget disease of the breast and extramammary Paget disease are intraepidermal adenocarcinomas characterized by large atypical and pale staining cells scattered throughout the epidermis either as single cells or in small clusters. Mammary Paget disease (MPD) resembles an eczematous eruption of the nipple and areola, and in almost all cases constitutes skin involvement by an
Fig. 3.20 Mammary Paget disease (MPD). Paget cells with large nuclei, prominent nucleoli and abundant pale cytoplasm permeate the entire epidermal thickness.
Fig. 3.21 Extramammary Paget disease (EMP). Paget cells often have a propensity for tracking along skin appendages.
ease are detected only on histologic examination of the nipple in a mastectomy specimen, without a clinically apparent lesion {1971}. No accurate epidemiologic data is available for EMP. It is a rare condition that comprises less than 2% of primary neoplasms of the vulva. EMP occurring in sites other than the vulva is even less common. In genital EMP, women are more commonly affected than men. Most patients are above the age of 60. Etiology MPD is almost always associated with an underlying carcinoma of the breast, and the etiology is the same as for breast carcinoma. The inciting factors for primary EMP are unknown. Secondary EMP is an expression of an underlying internal malignancy and the etiology parallels that of the underlying tumour. Localization MPD involves the nipple and areola and in advanced cases may extend to the adjacent skin. EMP involves apocrine gland bearing areas and is most common in the genital area, groin, perineum or perianal region. Axillae, eyelids and external auditory canals rarely may be involved. Clinical features Patients who present with MPD initially
develop erythema of the nipple and areola. The lesion then progresses to scaly, crusted thick plaques and ultimately to areas of erosion and ulceration. Patches and plaques are almost always unilateral and sharply circumscribed, and sometimes pruritic or painful. In approximately half of the cases a breast mass is palpable. Nipple retraction and serosanguinous discharge may be features of advanced cases with a large underlying carcinoma. Not all patients with MPD have clinical symptoms; 10-28% of cases are detected only on histologic examination in a mastectomy specimen {1971}. The differential diagnosis includes squamous cell carcinoma in situ and eczema. Once a diagnosis of MPD is established the patient needs to be evaluated with imaging studies and other procedures for breast carcinoma. If MPD is associated with a palpable tumour mass, the underlying carcinoma will be invasive in more than 90% of cases. If no tumour mass can be detected clinically, less than 40% of women will have invasive carcinoma. Patients with EMP most commonly present with pruritus or burning. The skin shows well-demarcated erythematous scaly patches and plaques, which may be ulcerated. Following a diagnosis of EMP the patient needs to undergo thorough examination to rule out an associated internal malignancy.
Tumour spread and staging MPD without invasive carcinoma on histologic examination is classified as carcinoma in situ (Tis). MPD with a contiguous or non-contiguous invasive component on histology is staged according to the invasive component using the guidelines for staging of breast carcinoma. Primary EMP is staged either according to the FIGO (Fdration Internationale de Gyncologie et dObsttrique) or the TNM system of the AJCC (American Joint Committee on Cancer) for vulvar tumours. After a long period of in situ growth EMP can eventually invade the dermis and acquire metastatic potential. Typically, invasive carcinoma associated with EMP first spreads to locoregional lymph nodes and ultimately may develop distant metastases. Secondary EMP is staged according to the criteria for the associated internal malignancy. Histopathology On histologic examination MPD and EMP are characterized by neoplastic cells with large nuclei, prominent nucleoli and abundant pale to amphophilic cytoplasm that are scattered throughout the entire epidermal thickness. These cells occur singly and in clusters and often are more numerous in the basal layers of the epidermis. Acinus formation may be present. Paget cells can contain cytoplasmic melanin pigment, a feature that should
Malignant tumours with apocrine and eccrine differentia 137
not imply melanocytic differentiation. The epidermis is often hyperkeratotic and acanthotic, especially if the disease has been chronic. Particularly in EMP, the tumour cells have a propensity to track along skin appendages. A dermal perivascular lymphohistiocytic infiltrate accompanies the epidermal changes. Paget cells are positive with conventional mucin histochemistry in 40-70% of cases {1297}. In MPD the associated in situ or invasive breast carcinoma is of ductal differentiation in the majority of cases. Lobular carcinoma only rarely gives rise to MPD. Histologically, EMP without an internal malignancy cannot be differentiated from those cases with associated neoplasm. The histopathologic differential diagnosis includes pagetoid squamous cell carcinoma in situ, superficial spreading malignant melanoma, pagetoid Spitz naevus, clear cells of Toker, pagetoid dyskeratosis, clear cell papulosis, sebaceous carcinoma, intraepidermal Merkel cell carcinoma, eccrine porocarcinoma, cutaneous T-cell lymphoma, Langerhans cell histiocytosis and epidermotropic metastasis. Immunoprofile The immunophenotype of MPD closely matches that of the underlying breast carcinoma {511}. Paget cells are practically always positive for low molecular weight cytokeratins (detectable by specific or broad spectrum cytokeratins such as CK7, CAM5.2 and AE1/AE3) and epithelial membrane antigen (EMA), variably positive for polyclonal carcinoembryonic antigen (pCEA) and lack lymphoid markers such as leukocyte common antigen (LCA) and CD3 {1036,1461}. Gross cystic disease fluid protein-15 (GCDFP-15) has been reported in approximately 50% of cases, similar to that of breast carcinoma in general {511}. As in breast carcinoma, reports of S100 reactivity are quite variable, ranging from 0-26% {1757,2548}. Approximately 5% of Paget cases are oestrogen receptor (ER) and/or progesterone receptor (PR) positive {511}.
The tumour cells in primary and secondary EMP are positive for simple cytokeratins (CAM5.2, AE1/AE3), EMA and CEA {1004,1539,1757,2548}. Immunohistochemistry can also suggest the presence of an associated internal malignancy, because primary EMP has the staining characteristics of an apocrine carcinoma and is almost always CK7 positive and gross-cystic disease fluid protein (GCDFP) positive, while CK20 is commonly negative whereas the opposite is true for EMP with associated internal malignancy. The cells in these latter cases are also mostly CK7 positive, but more often express CK20 and do not stain for GCDFP {851,852,1298,1461}. In EMP positive staining with CK20 and lack of staining with GCDFP should prompt an even more thorough evaluation for underlying malignancy. The most useful keratin markers for MPD and EMP are CAM5.2 and CK7 because they stain >90% of Paget cells but do not react with epidermal or mucosal keratinocytes, a characteristic that makes both antibodies very useful in the evaluation of surgical margins and invasion. Histogenesis MPD is almost always associated with an underlying carcinoma of the breast either in situ or invasive. MPD represents the retrograde extension of an underlying carcinoma into the epidermis, either in a contiguous fashion, through spread along the lactiferous ducts or through intraepidermal metastasis. Cases without underlying carcinoma exist but are exceptional {1159}. The etiology of these cases is speculative, but probably they are analogous to primary EMP, representing apocrine adenocarcinomas in situ, derived from Toker cells. Toker cells are cells with bland cytologic features and clear cytoplasm that have been identified by standard light microscopic means in ~10% of normal nipples {1461}. They are derived from lactiferous duct lining cells and preferentially cluster in the epidermis near lactiferous duct ostia. Primary EMP is an apocrine adenocarcinoma in situ that most likely arises from
intraepidermal cells of apocrine gland ducts. These cells, analogous to Toker cells of the nipple, have been recently demonstrated in the epidermis of vulvectomy specimens in association with mammary-like glands {2531}. In secondary EMP the disease represents migration of an underlying internal malignancy to the epidermis. Tumours associated with EMP include rectal adenocarcinoma, transitional cell carcinoma of the urethra and bladder, carcinoma of the Bartholins glands, prostate carcinoma, cutaneous adnexal carcinoma and carcinoma of the vagina and cervix. Prognosis and predictive factors The prognosis of MPD depends on the size and characteristics of the underlying breast carcinoma. Patients with MPD but without a clinically detectable breast mass have a much better prognosis. In a recent study, 61 patients with MPD and without palpable mass were treated with a cone excision of the nipple-areola complex and radiation therapy. Histologic examination revealed underlying DCIS in 93.3% of patients and Paget disease, only, in 7%. The recurrence rate at a median follow up of 6.4 years was 5.2% (1 patient with DCIS and 3 patients with invasive carcinoma) {242}. The majority of cases of EMP are not associated with another neoplasm and show a recurrence rate of approximately 30% after surgery, but do not metastasize. Around 10% of patients will develop invasive adenocarcinoma that may progress to metastatic disease {710}. The rate of an associated internal malignancy varies from 15% to 33% and is more common in perianal EMP than vulvar EMP {1024}. In these cases the associated tumour drives the clinical behaviour, treatment and prognosis.
Benign tumours with apocrine and eccrine differentiation
J. McNiff T.H. McCalmont L. Requena O. P. Sangeza
C. Vassallo R. Rosso G. Borroni E.J. Glusac R.O. Pichardo
Hidrocystoma
Definition Hidrocystomas are cystic proliferations of the sweat glands. They have either apocrine or eccrine differentiation, with the majority being of apocrine nature. Apocrine hidrocystomas are cystic adenomas that arise from the apocrine secretory coil, while eccrine hidrocystomas represent retention cysts of the eccrine cyst duct {607,1919,2047,2188}. ICD-O code 8404/0 to completely disappear with cold weather and atropine therapy {2236}. There is an increased incidence of hidrocystomas in hyperthyroid patients, perhaps related to hyperhidrosis {1270,1673}. Macroscopy The lesions are of variable size ranging from 0.5-1.0 cm, although lesions of up to 7.0 cm have been reported. Hidrocystomas are usually located in the dermis,
but in some cases they may be present in the subcutaneous fat. The cut surface reveals a well-circumscribed, unilocular or multilocular cyst. Histopathology Hidrocystomas can be uni or multilocular and are usually lined by a double layer of epithelium. The inner layer contains large columnar cells with eosinophilic cytoplasm which has luminal decapitation secretion, while the outer layer is flat and composed of myoepithelial cells. The term papillary apocrine gland cyst has been applied for hidrocystomas with papillary projections of epithelium into the lumen {1919}. Occasionally, hidrocystomas may show a single cystic cavity lined by one or two layers of flattened epithelium as a consequence of the pressure exerted by the contents of the cyst. In this circumstance, distinction from eccrine hidrocystomas, which have a similar lining, becomes impossible {671}.
Fig. 3.22 Hidrocystoma presenting as small, domeshaped lesion on the right side of the face, containing a clear fluid.
Synonyms Several and sometimes confusing terms have been used to designate hidrocystomas, to wit: apocrine gland cyst, papillary apocrine gland cyst {1919}, apocrine cystadenoma {1568}. Epidemiology Hidrocystomas are relatively rare and account for approximately one per thousand of submitted cutaneous biopsies {607}. They normally present as solitary lesions, however patients with multiple lesions have been observed. Hidrocystomas usually affect middle-aged or older individuals although rare examples have been described in children and adolescents; both sexes are equally affected. Localization Hidrocystomas have a predilection for the face and neck, mainly the periorbital area, but may also affect other parts of the body such as the perineum. Clinical features Hidrocystomas present as domeshaped, cystic firm papules or nodules, with a slightly blue colouration. In some cases the content of the cyst is brown or black. Etiology The exact cause of hidrocystomas is not known. They have been reported to be exacerbated with high temperatures and
Fig. 3.23 Hidrocystoma, papillary cystadenoma. A Example of the so-called "papillary apocrine gland cyst". These lesions are characterized by the presence of papillary projections of epithelium into the lumen. B The papillary projections contain a core of connective tissue and are lined by cuboidal epithelium. C This picture depicts a typical example of an apocrine hidrocystoma. The lesion is cystic and lined by a cuboidal epithelium. D At higher magnification the cyst is lined by a double layer of cuboidal cells with evidence of decapitation and secretion.
Benign tumours with aprocine and eccrine differentiation 139
Fig. 3.24 Syringoma. A Well circumscribed nodule within the upper dermis. B Tubules and cords of uniform epithelial cells in sclerotic stroma.
Immunoprofile Hidrocystomas express epithelial membrane antigen (EMA) and lysozyme in the cells of the cyst wall; carcinoembryonic antigen (CEA) decorates the luminal cells {1217}. The pattern of cytokeratin expression is variable {607,17444}; there is expression of cytokeratins 7,8,18,19 in the luminal cell layer and cytokeratins 1,5,10,14 in the basal and luminal cell layers. Smooth muscle actin (SMA) is present in the basal layer {607}. Human milk fat globulin 1 (HMFG) is expressed by the apocrine sweat gland only {607}. S-100 protein is positive in the secretory portion of normal eccrine glands and in the myoepithelial cells of apocrine glands {1678,2358}. Prognosis and predictive factors Complete excision is usually curative. Topical atropine or scopolamine has also been used {56,503,2236}. Avoidance of a hot environment or other factors that increase perspiration lessens the severity of these lesions {1668}.
Epidemiology Syringomas are common lesions, found more often in women than men. They appear more commonly in Asians than in other races. Syringomas usually arise in adolescence or early adulthood, but are most often biopsied in the 4th decade. Most are sporadic, though some eruptive and disseminated forms may be familial. Syringomas appear to be more common in Down syndrome. A clear cell variant has been associated with diabetes mellitus in many instances {800,2474}. Localization By far, the most common sites of involvement are the lower eyelids. Involvement of the upper cheeks is not uncommon. Unusual sites of involvement include the neck, chest, axillae, pubic area, periumbilical region, penis, vulva, hands and forehead. Unilateral linear lesions have been described {552}. Eruptive syringomas are typically numerous, widespread and may appear in crops {1388}. Clinical features The lesions are numerous, firm, smooth, dome-shaped, skin coloured or slightly yellowish papules, 1-3 mm in diameter, usually situated in skin of the lower eyelids. Syringomas are rarely solitary. Histopathology Syringomas are small lesions, restricted to the upper reticular dermis. They are composed of numerous small solid nests, cords and tubules of epithelial cells within a dense stroma of compactly arranged bundles of collagen, accompanied by relatively few fibrocytes. The epithelial aggregates are usually evenly distributed throughout the lesion. The
epithelial cells of syringoma show small nuclei, inconspicuous nucleoli and absent mitotic figures. Cytoplasm ranges from eosinophilic to clear. The epithelial cells within tubular structures show an inner layer of luminal cells and one or two rows of more peripheral cells. Tubular lumina may be distended, causing flattening of the inner most lining cells. Larger aggregates of cords and nests of cells may exhibit a comma-like or tadpole-like configuration. The cords, nests and tubules of syringomas branch and anastomose. Milia may be present, and these may rupture producing granulomatous inflammation and subsequent calcification. Syringomas may become confluent. Eruptive syringomas are similar to standard syringomas; however, the stromal component is sometimes less prominent. In most conventional syringomas some epithelial cells have pale cytoplasm. In some lesions, these cells predominate, and this pattern has been termed clearcell syringoma; it has frequently been associated with diabetes mellitus, but it may be seen sporadically. Differential diagnosis Desmoplastic trichoepitheliomas differ from syringomas by being larger, deeper, and composed of epithelial elements that show follicular differentiation. Superficial biopsies of microcystic adnexal carcinoma may greatly resemble syringoma. Microcystic adnexal carcinomas are larger, asymmetric and less circumscribed than syringoma. Virtually all microcystic adnexal carcinomas extend into subcutaneous fat or skeletal muscle, whereas syringomas are restricted to the upper two thirds of the reticular dermis.
Syringoma
Definition Syringomas are small benign adnexal neoplasms that are almost always multiple. They are composed of sweat gland epithelium (presumably eccrine) within densely sclerotic stroma. ICD-O code Synonyms Eccrine syringoma, tuberosum multiplex. 8407/0
lymphangioma
Prognosis Syringomas are benign. Association with or progression towards carcinoma has not been described.
Poroma
Definition Poromas are benign adnexal neoplasms with terminal ductal differentiation. Although historically considered a neoplasm of eccrine differentiation, poromas can show either eccrine or apocrine lineage. ICD-O code 8409/0
Synonyms Eccrine poroma, hidroacanthoma simplex, dermal duct tumour, syringoacanthoma Epidemiology Poromas usually present as solitary tumours on acral sites, although they can be seen in virtually any cutaneous location. Most poromas arise in middle age with no sex predilection. Uncommonly, multiple poromas are seen, either limited to palms and soles or in a widespread distribution, for which the term poromatosis has been applied. Clinical features Poromas typically manifest as domeshaped cutaneous papules, nodules or plaques, generally measuring less than 1 cm in diameter. Some lesions are highly vascular and may show a tendency to bleed, particularly on acral sites. Uncommonly, poromas are pigmented. Rapid growth has been reported during pregnancy {920}. Multiple poromas have developed after electron beam therapy for mycosis fungoides {1348} and occur-
Fig. 3.25 Poroma. A Broad tongues of uniform epithelium extend into the dermis from the undersurface of the epidermis. B Pigmented poroma illustrating ductal structures and fibrovascular stroma. C Clear cell change may be prominent in some poromas.
rence in areas of chronic radiation dermatitis has been reported {1802}. Occurrence of poroma within a naevus sebaceous has been documented {1133}. Histopathology Poromas are well-circumscribed tumours composed of a proliferation of uniform basaloid, cuboidal cells punctuated by focal ducts and occasional cysts. The epithelial cells of poromas typically extend from the lower epidermis into the dermis in broad columns. The epithelium of poromas is sharply demarcated from adjacent keratinocytes. Nuclei are small and regular, and cytoplasm is modest in amount. The cytoplasm often contains glycogen. Most poromas contain ductal structures lined by PAS positive diastaseresistant cuticles. Small areas of necrosis as well as mitoses are seen in otherwise banal poromas, and are of no prognostic significance. Foci of sebaceous differentiation may be observed. The stroma surrounding poromas is often richly vascular, and may contain granulation tissue. Architecturally, poromas show a spectrum of change from predominately intraepidermal lesions (hidroacanthoma simplex) to primarily dermal-based neoplasms (dermal duct tumour). Another rare variant has been termed syringoacanthoma, representing a clonal pattern
of poroma within an acanthotic epidermis with prominent surface keratinization. Differential diagnosis Histologically the differential diagnosis includes seborrheic keratosis, which typically shows keratinization with horn cysts, a more sharply demarcated lower border, and absence of ductal structures. Basal cell carcinoma may sometimes be considered histologically, but shows more obvious peripheral palisading, nuclear variability, and little or no glycogen. Histogenesis Poromas may show evidence of either eccrine or apocrine differentiation {970}. Immunohistochemical studies reveal that poroma cells express a cytokeratin phenotype similar to basal cells of the eccrine ducts in some cases {2466}. The absence of myoepithelial cells also suggests differentiation toward the excretory (ductal) component of sweat glands. Occurrence of poromas within folliculosebaceous lesions such as naevus sebaceous, and presence of sebocytes within poroma, implicates origin from apocrine glands in some cases {662, 970}. Genetics Some cases of poromatosis have been
Fig. 3.26 Intraepidermal variant of poroma. There are discrete nests of bland basaloid and cuboidal cells within the epidermis, associated with acrosyringium.
Benign tumours with aprocine and eccrine differentiation 141
Fig. 3.27 Syringofibroadenoma. A Clinical features of the verrucous, solitary type of syringofibroadenoma; a nodule localized on left sole of a 75-years old female, lasting for three years. B Eccrine syringofibroadenoma (Mascaro). Presents in many cases as a verrucous plaque. C Eccrine syringofibroadenoma (Mascaro). There are branching cords of small keratinocytes attached in multiple foci to the undersurface of the epidermis
associated with hidrotic ectodermal dysplasia {2519}. Rare cases of poroma have occurred in the setting of naevoid basal cell carcinoma syndrome {904}. Studies of p53 protein have shown high expression in some poromas as well as in some porocarcinomas, but staining is not correlated with duration of tumours {43}. Therefore, while p53 mutation may be involved in progression of some poromas to porocarcinoma, other oncogenes or factors are also likely play a role in malignant transformation of poromas. Prognosis Poromas are benign and simple excision is curative.
Localization Most of syringofibroadenomas arise on acral areas {498,685,769,2248,2313, 2344,2399}. Clinical features The most common clinical presentation is solitary, often verrucous papules or nodules {1529,2248,2313}. Unusual presentations include large plaques, linear lesions, and disseminated tumours {1259,2189,2248}. Etiology Occasionally, syringofibroadenoma can be associated with other entities, both inflammatory and neoplastic, including bullous pemphigoid {1720,1721}, lichen planus {780}, ulcers {1092,2399}, squamous cell carcinoma {1399}, sebaceous naevus {1719}, and chronic lymphoedema {806}. Based on the latter association and the presence of fibrous stroma, some authors consider syringofibroadenoma as a hyperplasia rather than a neoplasia {779,780,806,1092,1399,1719, 1720}. It may be associated with SchpfSchultz-Passarge syndrome {2189}, an autosomal dominant syndrome with palmoplantar keratoderma, hypodontia, and
eyelid hidrocystomas, whose genetic aberration has been localized to chromosome 13q {1259}. Histopathology Syringofibroadenoma is characterized by multiple anastomosing cords and strands of monomorphous cuboidal cells {26,1529}. The epithelial cords extend usually into the mid-dermis, and are embedded in a loose fibrovascular stroma. Rarely, a clear cell variant has been observed {781,2415}. Immunoprofile Light microscopy usually leads to a specific diagnosis. The tumour cells are usually positive for both keratin 6 and 19 as well as filaggrin {1108,1304,1742,1745, 2314}. Prognosis and predictive factors Syringofibroadenoma is a benign condition, and solitary lesions are cured by complete excision, while the treatment of multiple lesions is dependent on the size and location. Cases of syringofibroadenoma with foci of atypical squamous cells have also been described {255, 1215}.
Syringofibroadenoma
Definition Syringofibroadenoma is a rare benign eccrine tumour with anastomosing strands and fibrovascular stroma, first described by Mascaro {1529}. Multiple lesions of syringofibroadenoma are referred to as eccrine syringofibroadenomatosis {456,2189}. ICD-O code 8392/0
Synonyms Eccrine syringofibroadenoma {663}, eccrine syringofibroadenomatous hyperplasia {1721}, eccrine syringofibroadenomatosis {456,2189}, acrosyringeal adenomatosis {950}. Epidemiology Syringofibroadenoma is rare, with about 75 reported cases. It occurs primarily in older adults.
Fig. 3.28 Hidradenoma. A There is a multinodular solid and cystic proliferation of monomourphous adnexal keratinocytes. B Areas with cytoplasmic pallor are common (clear cell hidradenoma).
Fig. 3.29 Spiradenoma. A A pigmented and painful nodule on the posterior aspect of the arm. B These aggregations of neoplastic cells show round shape and smooth borders. C At higher magnification, numerous lymphocytes are seen scattered within the nodules of neoplastic epithelial cells. There are two distinct populations of neoplastic epithelial cells, dark and pale. Dark cells are small, basaloid cells with hyperchromatic nuclei and pale cells are larger with vesicular nuclei and ample pale cytoplasm.
Hidradenoma
Definition Hidradenoma is a benign adnexal neoplasm, closely related to poroma, that displays a limited degree of ductal differentiation. While historically considered eccrine, recent evidence suggests that hidradenoma can be either apocrine or eccrine {825,1543}. ICD-O code 8402/0
Clinical features Hidradenomas lack any distinctive clinical features, presenting as skin-coloured to red-brown nodules. Histopathology Hidradenoma is a mostly dermal neoplasm with a nodular, circumscribed pattern at scanning magnification. Sometimes an epidermal attachment can be identified. The intervening stroma is often sclerotic and may be highly vascularized, with ectatic vascular channels. Hidradenoma is composed of several types of cells: Clear or pale cells, which contain abundant glycogen, and show distinct cell membranes {578}. The number of clear cells varies from lesion to lesion. When these cells predominate, the name clearcell hidradenoma is appropriate {2544}. Squamoid cells are polygonal with a central vesicular nucleus and eosinophilic cytoplasm, and often are arranged in whorls {1774}. Mucinous cells are the least common component. They are large cells with fine basophilic granular cytoplasm. Cuboidal or columnar cells line the tubules and show evidence of apocrine differentiation {1427}. Transition between different types of cells is frequent. The cells are arranged in
sheets, punctuated by ducts and glandular areas which may show apocrine differentiation. Hybrid lesions including compact poroid cells with prominent ductal differentiation have been referred to as poroid hidradenomas. Prognosis Complete excision is curative.
Spiradenoma
Definition Spiradenoma is a benign dermal neoplasm that can show either eccrine or apocrine differentiation, and significant morphologic overlap with cylindroma. Historical annotation Chandeluz, in 1882, probably first described this tumour {765}. Unna first coined the term spiradenoma. In 1956 Kersting and Helwig published the classic paper on spiradenoma in 136 patients {1250}. Additional series of spiradenoma have since been published {12,1496}. ICD-O code 8403/0
Synonyms Clear cell hidradenoma, nodular hidradenoma, poroid hidradenoma, acrospiroma, solid-cystic hidradenoma {825,980,1374}. Epidemiology Hidradenomas are sporadic with no sex predilection. Most develop in adults, but childhood onset has been documented {715,1652}. Hidradenoma can also arise as a secondary neoplasm with naevus sebaceous. Localization Hidradenomas commonly develop on the scalp, trunk, and proximal extremities, and rarely on the hands and feet. Eyelid lesions have also been noted {911}.
Localization Most spiradenomas appear on the face
Benign tumours with apocrine and eccrine differentiation 143
Fig. 3.30 Cylindroma. A There is a puzzle-like array of basaloid cells with relatively sharp circumscription of individual nodules. The larger nodules on the left show trabecular internal structure, suggesting overlap with spiradenoma. B The nests are outlined by a thick rim of PAS-positive and diastase-resistant basement membrane material.
and upper trunk, but they can also affect other sites. Clinical features Usually, spiradenoma appears as a solitary, well-circumscribed, firm nodule, measuring usually less than 1 cm, but giant variants {546} and multiple lesions have also been described {1725}. Unusual cases show multiple spiradenomas arranged in a zosteriform linear pattern {926,2162}. Spiradenoma appears in adult life, although there are also reports of congenital cases {2091}, and in one patient spiradenoma developed within a naevus sebaceous of Jadassohn {2154}. Pain is one of the main clinical characteristics of spiradenoma {926, 2091,2154}. The mechanism of pain or tenderness in spiradenoma is not clear. Histopathology At low power magnification, spiradenoma appears as a solid neoplasm composed of a single or few nodules of basaloid cells. These aggregations are round with smooth borders and involve the full thickness of the dermis, sometimes extending into the subcutaneous fat. Often, the intervening stroma is oedematous with ectatic vessels {546}. Dilated vessels rimmed by sclerosis have been interpreted as ancient changes due to long-standing lesions {2229}. Another characteristic finding is the presence of abundant lymphocytes scattered within the tumour nodules. At higher magnification, two distinct populations of neoplastic epithelial cells can be seen, dark and pale. Dark cells are small,
basaloid cells with hyperchromatic nuclei located at the periphery, whereas pale cells, which are larger with vesicular nuclei and ample pale cytoplasm, tend to be near the centre of the clusters. Tubules lined by two rows of epithelial cells may be found within the tumour nodules. A characteristic feature is the presence of eosinophilic PAS positive globules throughout the entire neoplasm, sometimes surrounded by neoplastic cells in pseudorosette fashion. These globules are composed of basement membrane material. Sometimes the stroma shows striking oedema. Spiradenoma in children may show a different histopathologic pattern. The neoplastic cells appear more immature, making the distinction between clear and dark neoplastic epithelial cells difficult, and the neoplasm may be misinterpreted as a mesenchymal neoplasm {1206}. Spiradenoma and cylindroma show significant morphological overlap. In some patients with multiple lesions, some tumours show features of spiradenoma, and others features of cylindroma. This supports the notion that spiradenoma and cylindroma are closely related, probably representing two morphologic expressions of the same basic neoplastic process {846,2280}. Immunoprofile The tumour cells express cytokeratins, and the tubular structures are CEA positive {1801,2465}. Inflammatory cells scattered within the neoplastic aggregations have been identified as abundant T lymphocytes and Langerhans cells.
Histogenesis The histochemical and immunohistochemical studies have not clarified the histogenesis of spiradenoma. The frequent association of spiradenoma and cylindroma, a likely apocrine neoplasm, and the sporadic association of spiradenoma with neoplasms with follicular differentiation such as trichoepithelioma {2500}, support an apocrine line of differentiation for spiradenoma on the basis of the common embryologic origin for the three elements of the folliculo-sebaceous-apocrine unit. This is furthermore supported by some examples of spiradenoma that show decapitation secretion in the cells lining the luminal border of the tubular structures. Therefore, the qualifying term of eccrine that almost invariably is applied to spiradenoma is inaccurate. Prognosis and predictive factors Spiradenoma is a benign neoplasm. Because of the sharp demarcation of the tumour from the surrounding stroma, excision is easily accomplished. Several examples of carcinomas arising in longstanding spiradenomas have been described. In those instances, enlargement of a nodule that had been stable for many years seems to be the sign of malignant transformation {89,240,539, 699,884,2602}. It appears to be accompanied by increased expression of p53 protein {239}.
Fig. 3.31 Tubular adenoma. A A skin-coloured smooth surfaced nodule on the left parietal scalp. B Multiple irregularly shaped tubular glandular structures within a partly sclerosed stroma. C Banal appearing tubular glandular elements lined by a double layer of epithelial cells within a sclerosed stroma. The peripheral layer is cuboidal in appearance and the luminal layer demonstrates decapitation secretion. The lumina are filled with cellular debris and granular eosinophilic material.
Cylindroma
Definition Cylindroma is a relatively undifferentiated benign adnexal neoplasm with a mosaic microscopical pattern. Cylindroma commonly occurs as a hybrid with spiradenoma, an event that has been referred to as cylindrospiradenoma or spiradenocylindroma {301,846,1543,1600}. ICD-O code 8200/0
Cylindroma can rarely be found as a secondary neoplasm within naevus sebaceous. Histopathology Cylindroma is a mostly dermal and sometimes subcutaneous neoplasm with a multinodular, circumscribed pattern at scanning magnification. Individual nodules are composed of mosaic nests of undifferentiated basaloid cells with small darkly-staining nuclei and scant cytoplasm; individual nests fit tightly and neatly within larger nodules in a pattern that has been likened to that of a jigsaw puzzle. The nests of cylindroma are commonly surrounded by a rim of densely eosinophilic PAS-positive basement membrane material, and the nests are also punctuated by small round droplets with similar staining qualities. Hybrid lesions with areas of cylindroma and spiradenoma in juxtaposition are not uncommon {301,846,1543,1600}. Immunoprofile and histogenesis Refer to the previous chapter on spiradenoma. Prognosis and predictive factors Simple excision is usually curative. Malignant transformation is extremely uncommon.
ICD-O code Tubular adenoma 8211/0 Tubular papillary adenoma 8263/0 Synonyms Apocrine adenoma, tubular adenoma, tubulopapillary hidradenoma, papillary tubular adenoma Epidemiology Tubular apocrine adenomas occur sporadically with a female predilection {1361}. A broad age group may be affected {1361}. Some neoplasms may occur in association with a syringocystadenoma papilliferum {76,489,1111, 2364} and can also arise within an organoid naevus {1111,1361,2394}. Localization Tubular apocrine adenomas commonly occur on the scalp and less often at other sites including the leg, trunk, axillary and anogenital areas {1361}. Clinical features Tubular apocrine adenomas present as asymptomatic solitary nodules that are skin-coloured to pink-red in appearance with either a smooth or irregular appearance {1361}. Most tumours range in overall dimension between 1 to 2 cm but rarely may be as large as 7 cm {1361}. Histopathology Tubular apocrine adenomas are well-circumscribed dermal neoplasms that may extend into the subcutis. They have an overall lobular architecture and are typically encased by a fibrous stroma. The lobules consist of multiple irregularly shaped tubular structures that have a double to several layered epithelial lin-
Synonyms Cylindrospiradenoma {301}, spiradenocylindroma {1600} Epidemiology Cylindromas may be solitary or multiple, arising on a sporadic basis or as part of Brooke-Spiegler syndrome. There is no sex predilection. Etiology The etiology is unknown. A link to chromosome 9 seems likely for multiple spiradenomas and cylindromas in the context of the Brooke-Spiegler syndrome, as the gene has been mapped to 9p21 {951,1538}. Localization The vast majority of cylindromas occur on the scalp or face, especially in the vicinity of the ear. Uncommonly, cylindromas develop on the trunk or proximal extremity. Clinical features Cylindromas are typically smooth, domeshaped hairless red-brown papules and nodules. Extensive scalp involvement can create clinical morphology resembling a headpiece (turban tumour).
Tubular and tubular papillary adenoma

Definition Tubular apocrine adenoma is a benign dermal adnexal neoplasm demonstrating apocrine differentiation that typically occurs in a broad age group of women on the scalp region.
favoured sites; those on the scalp are typically alopecic. Syringocystadenomas may develop during puberty in a preexisting naevus sebaceous, and at least one-third are associated with an underlying organoid naevus. Histopathology Histologically, endophytic invaginations of epithelium extend from the epithelial surface into the dermis. Typically squamous epithelium is present at the surface of the invaginations, and is contiguous with a double layer of cuboidal and columnar epithelium in the deeper portions of the lesion. Within the dermis, broad villous projections protrude into cystic spaces. Columnar epithelium is present toward the lumen of the spaces, and simple cuboidal epithelium can be seen at the periphery. Decapitation secretion of luminal cells is a frequent finding. Plasma cells are consistently numerous within the stroma, and are a highly reproducible finding in the stroma of syringocystadenomas. The differential diagnosis includes hidradenoma papilliferum, which differs clinically by location in the perineal region, and histologically by dermal nodules showing a more complex papillary growth pattern, and absence of plasma cells in the stroma. The epithelial lining of the two lesions shows histologic overlap, however. Precursor lesions Approximately one-third of cases arise in organoid naevi. Histogenesis Syringocystadenomas show differentiation that is predominantly apocrine in pattern, but eccrine origin has been suggested in some cases, as exemplified by immunohistochemical labelling with eccrine marker IKH-4 {1109}. An intriguing finding is the presence of IgA and secretory component within the epithelial cells in syringocystadenomas, and IgA and well as IgG within the plasma cells {2420}. This observation suggests that plasma cells are attracted to tumour epithelium via a mechanism similar to that used by glands of the normal secretory immune system. Somatic genetics Allelic deletions of the patched gene 9q22 and loss of heterozygosity at 9p21
Fig. 3.32 Syringocystadenoma papilliferum. A Keratinizing squamous epithelium at the surface merges with columnar epithelium in the deeper portions of the tumour. B Papillary projections are lined by pseudostratified columnar epithelium, and plasma cells are typically noted in the stroma.
ing. The peripheral epithelial layer consists of cuboidal to flattened cells (myoepithelial) and the luminal layer of columnar cells that demonstrate decapitation secretion. In some tubules papillary cellular extensions that are devoid of stroma project into the lumina. Additionally, cellular debris and eosinophilic granular material are identified within some lumina {1361}. The neoplasm lacks cytologic atypia and mitotic activity. Overlying epidermal hyperplasia may be present. In those neoplasms that occur in conjunction with syringocystadenoma papilliferum {76,489,2364}, the tubular adenoma component is typically present underlying the syringocystadenoma component. The differential diagnosis includes apocrine adenocarcinoma and papillary eccrine adenoma. In contrast to apocrine adenocarcinoma tubular apocrine adenomas lack cytologic atypia, are well circumscribed and possess a peripheral myoepithelial layer {1751}. Tubular apocrine adenomas resemble papillary eccrine adenomas in many respects and previously these were believed to be related neoplasms {489}. However on the basis of morphologic criteria (papillary eccrine adenomas lack decapitation secretion) and enzyme histochemistry and ultrastructural analysis demonstrating differences in differentiation (apocrine versus eccrine) they are now believed to represent distinct neoplasms. In some instances both eccrine and apocrine differentiation may be observed making a distinction between these neoplasms impossible {771}. The terms tubulopapillary hidradenoma {705} and papillary tubular adenoma {2335} have been suggested for cases with apocrine and eccrine differentiation.
Histogenesis Enzyme histochemistry {1361} and ultrastructural analysis {1361,2394} have demonstrated tubular apocrine adenomas to be of apocrine differentiation. Prognosis Tubular apocrine adenomas are benign slow-growing neoplasms. Simple excision is curative.
Syringocystadenoma papilliferum
Definition Syringocystadenoma papilliferum is a benign adnexal neoplasm that occurs in association with an organoid naevus such as naevus sebaceous in at least one-third of cases. ICD-O code Synonmys Syringoadenoma Epidemiology Syringocystadenoma papilliferum occurs with equal frequency in both sexes. It is a tumour of childhood or adolescence, with many examples noted at birth. These lesions tend to increase in size at puberty, and sometimes multiply in number as well as becoming more papillomatous over time. Clinical features The majority of syringocystadenomas affect the head and neck area, typically as one or more warty papules, sometimes in a linear array, or as a solitary grey or red plaque. Scalp and neck are 8406/0
Fig. 3.33 Hidradenoma papilliferum. A Hidradenoma papilliferum of the vulva. A polypoid exophytic lesion involving the left labius majus of an elderly woman. B The neoplasm shows a prominent papillary pattern. C Columnar cells shows evidence of decapitation secretion in their luminal border.
(p16) have been reported in syringocystadenoma papilliferum {281}. Prognosis and predictive factors Syringocystadenonas are benign and simple excision is curative.
Hidradenoma papilliferum
Definition Hidradenoma papilliferum is a benign cystic and papillary neoplasm that almost always develops in the vulval and perianal regions of middle-aged women. ICD-O code 8405/0
Epidemiology Most cases appear in women, although there are also reports in males {588, 1441,1697,2421}. The neoplasm is rare in Black patients. The age of presentation ranges from 20-90 years {2428, 2435}. Localization The skin of the vulva and perianal regions are the most frequently involved areas {588,1106,1441,1565,1568,1697, 2324,2421}, although rare examples of extra-genital or ectopic hidradenoma papilliferum have been reported on postauricular skin {247}, eyelids {1106, 1697,2056,2421}, external auditory canal {1718}, face {1106,1697} scalp {845}, axilla {1106,2421}, upper limb {2421}, back {727,1106} and thigh {2421}. Clinical features The lesion appears as a slow-growing cystic dermal nodule, usually asymptomatic, although it sometimes ulcerates and bleeds. The neoplasm is a unilateral skin-coloured nodule, papule or polypoid exophytic lesion, most commonly located on the labius majus.
Histopathology At scanning magnification, hidradenoma papilliferum consists of a cystic neoplasm composed of elongated tubules and large papillary structures with a frond-like pattern. The papillae are composed of a central axis of connective tissue lined by two layers of epithelial cells. The basal layer is composed of palestaining cuboidal myoepithelial cells and the luminal layer is made up by columnar cells with decapitation secretion. The cystic cavity and the lumina of the tubular structures contain apocrine secretions in the form of eosinophilic homogeneous material. The epithelial cells at the periphery are flattened, and decapitation secretion is less evident, as a consequence of the pressure exerted by the cyst contents. The stroma surrounding the cystic cavity is composed of compressed fibrous tissue that is separated from the normal adjacent dermis by clefts. These clefts are responsible for the tendency of the neoplasm to shell out easily after incision of the epidermis. In contrast with syringocystadenoma papilliferum, hidradenoma papilliferum is not connected with follicular infundibula and there are not plasma cells in the axis of connective tissue of the papillations. Sometimes, neutrophils are scattered within the connective tissue framework. Immunoprofile Immunohistochemical studies demonstrated that epithelial cells lining the papillations express low-molecular weight cytokeratins. The luminal border of the cells lining tubular structures is also decorated by carcinoembryonic antigen, epithelial membrane antigen and gross cystic disease fluid protein-15. Immunostains for S-100 protein and high-molecular-weight keratins are nega-
tive {2257}. Neoplastic epithelial cells lining tubules and papillations also express strong immunoreactivity for androgen and oestrogen receptors {1739}. Histogenesis Both the histopathologic and ultrastructural characteristics of hidradenoma papilliferum support an apocrine line of differentiation, although some authors have postulated the possibility of origin from Wolffian ducts or accessory mammary glands {576,1633}. Prognosis and predictive features Hidradenoma papilliferum is a benign neoplasm cured by simple excision. Malignant transformation is a very uncommon event {588,1730,2274,2460}. A case of adenosquamous carcinoma of the vulva developing from a pre-existing hidradenoma papilliferum has also been reported {142}.
Mixed tumour (chondroid syringoma)

Definition Cutaneous mixed tumours are benign adnexal tumours of skin composed of epithelial and stromal elements with a wide spectrum of patterns. These tumours are histologically analogous to mixed tumours of the salivary gland, but lack the tendency for local recurrence seen in the latter lesions. ICD-O code 8940/0
Synonyms Chondroid syringoma, mixed tumour of skin. Epidemiology Mixed tumours most often occur as solitary slowly growing nodules on the head
Fig. 3.34 Mixed tumour (chondroid syringoma). A Well-circumscribed mixed tumour with branching tubules and myxochondroid stroma. B Mixed tumour with epithelial tubules embedded in a myxoid and hyaline stroma. C Predominately ductal epithelial pattern of mixed tumour.
and neck of adults, although other sites may be affected. There is a male predilection. Most lesions are between 13 cm in diameter, although examples as large as 6 cm have been reported {1182}. Clinical features Cutaneous mixed tumours present as asymptomatic dermal nodules, with no specific distinguishing clinical characteristics. Histopathology At low power, cutaneous mixed tumours are well-circumscribed lesions located in the dermis and/or subcutis. A biphasic growth pattern can be readily detected, with epithelial elements embedded within a myxoid, chondroid, or fibrous stroma. The epithelium often shows a pattern of branching tubules, sometimes with decapitation secretion suggesting apocrine differentiation. Solid cords and islands of epithelium as well as single cells may also be present. In some cases, the epithelial elements are composed of small non-branching tubules that may contain eosinophilic cuticles. Follicular differentiation occurs in some mixed tumours, in the form of follicular germinative cells, shadow cells, or sebocytes. Mixed tumours may exhibit clear cell change within the epithelial cells. In an estimated 40% of cases, mixed
tumours contain hyaline cells characterized by an ovoid shape, dense groundglass or hyaline-like cytoplasm, and an eccentric nucleus {85}. The cells resemble plasma cells, and have been called plasmacytoid cells. In some cases, hyaline cells are the predominant cell type, leading to the term hyaline-cell rich chondroid syringoma {735}. The presence of hyaline cells appears to be of no prognostic significance, although such cells may present a diagnostic challenge to the unsuspecting pathologist {735}. Immunoprofile Immunohistochemical studies reveal staining of the inner layer of epithelial cells with cytokeratin, CEA, and EMA, and staining of the outer cellular layer with S100 and vimentin {2559}. The stroma of mixed tumours usually comprises at least half of the lesion, and may show variable patterns of differentiation, including myxoid, fibroblastic, fibrocartilagenous, chondroid, and even osteoid components. Combinations of matrix components are the rule. Despite the name chondroid syringoma, chondroid areas may be absent in the stroma. The stroma stains strongly for alcian blue with hyaluronidase resistance. Differential diagnosis In mixed tumours where stroma predominates, the differential diagnosis includes
entities such as myxoma. In other lesions with abundant epithelial elements, the differential diagnosis includes benign adnexal tumours such as hidradenoma and syringoma, depending on the pattern of epithelial growth. Histogenesis It is generally accepted that there are both apocrine and eccrine variants of mixed tumours. Ultrastructural studies confirm that myoepithelial cells surround the epithelial cells, and appear to produce the stromal components of the lesions {2423}. The stroma of mixed tumours contains matrix components such as types II and IV collagen, tenascin, fibronectin, and laminin {773}. Ultrastructural and immunohistochemical studies of hyaline cells in mixed tumours suggest these cells derive from both the epithelial and stromal components of the lesions, possibly representing a regressive process {85}. Prognosis Cutaneous mixed tumours are benign lesions cured by simple excision.
Malignant tumours with follicular differentiation
S. Kaddu L. Requena
Pilomatrical carcinoma
Definition Pilomatrical carcinoma is the malignant counterpart of pilomatricoma. ICD-O code 8110/3
occurs mainly in middle aged and elderly individuals, may represent an intermediate precursor lesion. Localization Pilomatrical carcinomas mostly occur in the head and neck, upper extremities and buttocks. Rare tumours have been reported in the axilla and inguinal regions. Clinical features The clinical appearance of pilomatrical carcinoma is generally not distinctive. Patients show solitary, occasionally ulcerated or fungating nodules ranging in size from 1-10 cm in diameter. Skin nodules are often of long duration ranging from several months to years before diagnosis, although occasional cases of recent onset and a history of rapid growth have been reported. Histopathology The tumour is a large, asymmetrical, poorly circumscribed dermal or dermalsubcutaneous mass composed of several, irregularly shaped and variously sized
Synonyms Pilomatrix carcinoma, matrical carcinoma, invasive pilomatrixoma, malignant pilomatrixoma, matrix carcinoma. Epidemiology Pilomatrical carcinoma is an extremely rare tumour. Most cases present in adults with a broad age range {28,804,954, 2064}. The mean age at the time of diagnosis is about 48 years. The male to female ratio is 2:1. Etiology The majority of pilomatrical carcinomas develop de novo, although malignant transformation from a pre-existing pilomatricoma has been reported {2064}. It is conceivable that proliferating pilomatricoma, a variant of pilomatricoma that
aggregations of basaloid cells (matrical and supramatrical cells) {28,804,954, 2064}. Foci of cornified material containing shadow cells are characteristically observed within the basaloid cell aggregations. Some neoplasms show a variable desmoplastic stroma surrounding the basaloid cell aggregations. Focal connections of basaloid cell aggregations to the overlying epidermis and/or ulceration are often noted. Basaloid cells exhibit hyperchromatic nuclei, with one or more prominent nucleoli and illdefined cytoplasmic margins as well as variable numbers of occasionally atypical mitotic figures (up to 10 mitoses per high-power field). Foci of geographical necrosis, calcification and ossification are observed. Mitotic activity is not a reliable indicator of malignancy, because mitoses are common in pilomatricoma. Other parameters, such as an infiltrative growth pattern, as well as angiolymphatic, perineural, and bone invasion, are more reliable features {804,2064}. Immunoprofile Immunohistological studies have previ-
Fig. 3.35 Pilomatrical carcinoma. A The neoplastic cells are present in apposition to the epidermis. B A large mass of shadow (ghost) cells is present. The clear cells have more nuclear pleomorphism than in the pilomatricoma.
Malignant tumours with follicular differentiation 149
evidenced by involvement of regional lymph nodes, lungs and/or bone.
Proliferating tricholemmal tumour

Definition Proliferating tricholemmal tumour is a solid-cystic neoplasm that shows tricholemmal differentiation similar to that of the isthmus of the hair follicle. ICD-O code 8103/1
Fig. 3.36 Proliferating tricholemmal tumour. A large tumour on the scalp of an elderly woman.
ously revealed keratin staining in both basaloid and shadow cells {556}. Prognosis and predictive factors Treatment of choice is by surgical excision with adequate margins. Mohs micrographic surgery technique may be useful in treating some patients. Pilomatrical carcinoma is a mainly locally aggressive tumour which often recurs if not completely removed but very rarely shows distant metastases. Metastatic spread is
Synonyms and historical annotation Epidermoid carcinoma in sebaceous cyst {252,416} subepidermal acanthoma {1458}, proliferating epidermoid cyst {1152}, invasive hair matrix tumour of the scalp {1910}, trichochlamydocarcinoma {1053}, giant hair matrix tumour {583}, proliferating tricholemmal cyst {321}, proliferating pilar cyst {68,92}, proliferating follicular cystic neoplasm {23}, proliferating tricholemmal cystic squamous cell carcinoma {1631}, proliferating isthmic cystic carcinoma. These different names reflect the distinct histogenetic and biologic interpretations for this neoplasm among different authors. Epidemiology The neoplasm is more frequent in women than in men and most patients are elderly {2069}.
Fig. 3.37 Proliferating tricholemmal tumour. The lobules of the neoplastic epithelium show tricholemmal keratinization, characterized by peripheral palisading of small basaloid cells and large keratinocytes with ample eosinophilic cytoplasm that develop abrupt keratinization without previous granular layer, resulting in compact orthokeratotic eosinophilic keratin. This type of keratinization is similar to that of the outer sheath at the level of the isthmus of the hair follicle.
Localization More than 90% of the lesions are situated on the scalp. Other described locations, in decreasing order of frequency, include face, trunk, back and forehead {2069}. Clinical features The tumour is a solitary, multilobular, large, exophytic mass, which may develop within a naevus sebaceous {866, 1874}. Multiple lesions are very rare. The size ranges from 2-10 cm in diameter, although lesions up to 25 cm in diameter have been described {407}. Alopecia and ulceration can be found. Macroscopy The lesions often show a multilobular appearance. The cystic structures often contain compact keratin and calcified material. Histopathology Proliferating tricholemmal tumour occurs on a morphologic continuum. On one end of the spectrum, it consists of a wellcircumscribed solid and cystic neoplasm which involves the dermis and sometimes extends to the subcutaneous tis-
Fig. 3.38 Proliferating tricholemmal tumour. At scanning power the neoplasm appeares as a well-circumscribed cystic neoplasm involving deeper dermis and subcutaneous tissue of the scalp.
sue. In addition to the typical features of a tricholemmal (pilar) cyst, this tumour shows prominent epithelial infoldings into the cyst lumen. The epithelium shows peripheral palisading of small basaloid cells arranged along a thick vitreous membrane, differentiating towards large keratinocytes with ample eosinophilic cytoplasm and abrupt keratinization without a granular layer. Often, areas of calcification and abundant cholesterol crystals are seen within the compact eosinophilic keratin. The neoplastic cells are monomorphous without significant cytologic atypia and with only rare mitoses {1135,1724}. On the other end of the morphologic spectrum are neoplasms with malignant features such as invasive growth extending beyond the confines of the cyst wall coupled with nuclear pleomorphism and high mitotic activity. These areas may be indistinguishable from squamous cell carcinoma. Additional findings include shadow cells as an expression of focal matrical differentiation similar to that of pilomatricoma {1726}, areas of sebaceous and apocrine differentiation {2021}, and spindle cells {1649}.
Differential diagnosis includes tricholemmal cyst, which lacks the multilobular architecture, as well as proliferating epidermoid (infundibular) cyst {2069}. The latter occurs most commonly in the anogenital region of male patients and shows a cystic cavity lined by stratified squamous epithelium with infundibular keratinization. Up to 20% of the lesions may undergo malignant transformation into squamous cell carcinoma {2069}. Differentiation between proliferating tricholemmal tumour and proliferating infundibular cyst is straightforward, because the former shows tricholemmal keratinization, whereas the latter has mainly infundibular keratinization. Tricholemmal carcinoma should also be considered. Immunoprofile Proliferating tricholemmal tumour expresses fetal hair root cytokeratin, as well as cytokeratin 7 {933}. Histogenesis The pathogenesis remains unknown. In some cases, human papillomavirus has been implicated in the etiology {23}. It is
unclear if proliferating tricholemmal tumours arise de novo or from pre-existing tricholemmal cysts {1631,1847}. Prognosis and predictive factors Proliferating tricholemmal tumours without atypical features generally behave in a benign fashion {762}. Yet, complete excision is recommended to avoid recurrences, and to allow for complete histopathological evaluation. Tumours with an invasive growth pattern or cytologic atypia have an unpredictable course. They may be locally aggressive, recur, or metastasize {68,178,982,1017, 1537,1572,1727,1728,1773,2311,2486}. For this reason, it has been suggested that even the classical benign lesions are squamous cell carcinoma {1631}.
Malignant tumours with follicular differentiation 151
Benign tumours with follicular differentiation
M. A. Hurt S. Kaddu H. Kutzner
B. Cribier T. Schulz W. Hartschuh
Trichoblastoma
Definition Trichoblastoma is a benign neoplasm differentiated toward the trichoblast, i.e., the folliculo-sebaceous-apocrine germ, or follicular germ, for short. In many cases, advanced follicular differentiation can be present also {28,989,1083}. ICD-O code 8100/0
The differential diagnosis is non-specific for solitary lesions, but includes the angiofibroma of tuberous sclerosis when multiple. Histopathology Trichoblastic epithelial components associated with stereotyped stroma, chiefly the follicular papilla, must be present to establish the diagnosis with surety. There are five patterns; these can be mixed in any given neoplasm. Large and small nodular trichoblastomas are usually circumscribed, sometimes subcutaneous, and contain a uniform distribution of solid trichoblasts with follicular papillae. In some cases, the follicular papillae are not papillary in that they fail to invaginate into the epithelial components of the germ. The epithelial cells are deeply basophilic, uniform, and overlap each other usually. Melanocytes can be prominent within the epithelial areas in some cases. Some cases have nodules that are lymphocyte-rich, a pattern termed originally lymphadenoma {1561,2053}. It should be noted that, rarely, lesions with a pattern similar to nodular trichoblastoma are really trichoblastic (basal cell) carcinomas that mimic trichoblastoma. While it is not completely understood what are all the factors that
Synonyms Trichoepithelioma, trichoblastic fibroma, trichogenic trichoblastoma, lymphadenoma (adamantinoid trichoblastoma), trichogerminoma, sclerosing epithelial hamartoma, Brooke-Fordyce disease, Brooke-Spiegler disease. Clinical features Trichoblastomas, as a rule, are solitary, small papules that occur on any hair follicle-bearing location (usually head and neck), at any age, and can affect either sex. They can also present as multiple centrofacial papules or nodules, particularly in the diseases of Brooke-Fordyce and Brooke-Spiegler. The size of an individual neoplasm can vary from a few millimetres to several centimetres, but most are less than 1 cm in diameter. Most are skin-coloured and ulcerated only rarely.
differentiate these lesion from trichoblastoma, one seems to be that the carcinomas infiltrate through skeletal muscle or other deep structures while there is a conspicuous absence of the usual stroma present in a classic nodular trichoblastoma. Rare examples with this pattern have metastasized {1960}. Retiform trichoblastomas are reticulated, with large fenestrations containing follicular stroma. Cribriform trichoblastoma is the most common pattern when the neoplasms are multiple, characteristic of BrookFordyce disease. The trichoblasts are usually fenestrated, but with small fenestrations compared to the retiform pattern. Racemiform trichoblastoma contains epithelial nests that simulate clusters of grapes. This results in stromal components that connect with the surrounding stroma rather than being isolated from it in fenestrations. Columnar trichoblastoma (desmoplastic trichoepithelioma) occurs most commonly as a solitary depression on the face of a young woman. As a rule, these neoplasms are confined to the superficial dermis. They contain stereotyped, thin strands of epithelium compressed by dense stroma. Small trichoblasts can be seen in some cases, but are less common compared to conventional forms of
Fig. 3.39 Trichoblastoma. A Large nodular trichoblastoma. Note the circumscription. Melanin pigmentation is present in this lesion. B Cribriform trichoblastoma. At scanning magnification, there are small groupings of basophilic cells containing small fenestrations of stroma.
Fig. 3.40 Trichoblastoma. A This trichoblast has a typical follicular "papilla" that does not extend cleanly into an invaginated epithelial component of the follicular germ. B Compared to the usual types of trichoblasts seen in nodular trichoblastoma, this trichoblastic carcinoma has diminished mesenchymal stroma, specifically diminished mesenchyme of the follicular papilla. C Trichoblast containing a superficial follicular papilla that protrudes into an invaginated follicular germ. This is a fundamental finding in trichoblastomas of any pattern. D Retiform trichblastoma. This reticulated pattern is seen often in large, solitary lesions. E This sievelike pattern is commonly present in the small centrofacial lesions of Brooke-Fordyce disease and is the pattern known classically "trichoepitheliom". F Groupings of follicular germinative cells that branch out, mimicking a "cluster of grapes". Absence of sieve-like areas seen in the cribrifom pattern.
trichoblastoma. The differential diagnosis includes morpheiform basal cell carcinoma, microcystic adnexal carcinoma, and, rarely, metastatic carcinoma from breast. Thus, superficial biopsies of such lesions should be investigated thoroughly, and additional biopsy or excision should be requested for cases in which the diagnosis is uncertain. Immunoprofile Trichoblastomas, as a rule, cannot be differentiated from basal cell (trichoblastic) carcinoma based solely on specific expression of cytokeratins. The presence of presumed Merkel cells within a neoplasm, however, does seem to favour trichoblastoma over basal cell carcinoma {1349}. Some trichoblastomas can contain zones of ductal differentiation; when this occurs, markers, such as CEA will highlight those areas {2398} but they will not aid in establishing the diagnosis. Uncommonly, excessive pigmentation is seen in nodular trichoblastoma, and these lesions contain markers for melanocytes {1199}, but they are nonspecific for the diagnosis, as basal cell (trichoblastic) carcinoma can have similar findings. Desmoplastic trichoepithelioma contains AE14, EMA, and Leu-M1 (CD15) focally,
but is negative for CEA and S100 {2511}. CK 5, 8, 14 and 15 have been identified in some cases {2555}. It can be differentiated from morpheiform basal cell carcinoma and microcystic adnexal carcinoma, in most cases, by applying CK20, which marks neuroendocrine cells in desmoplastic trichoepithelioma, but not in basal cell carcinoma or microcystic adnexal carcinoma {13}. Furthermore, CK7 is usually positive in breast carcinoma metastatic to skin and in microcystic adnexal carcinoma, but not in desmoplastic trichoepithelioma. Stromelysin 3 has also been identified in the stroma of morpheiform basal cell carcinoma, but not in the stoma of desmoplastic trichoepithelioma {2346}. Somatic genetics Multiple trichoblastomas (BrookeFordyce disease) are transmitted as an autosomal dominant trait linked to chromosome 9p21 {6,951}. Solitary (sporadic) trichoblastomas have been linked, in some cases, to 9q22.3 {1538}, the same locus for the naevoid basal cell carcinoma syndrome {4}. Familial multiple trichoblastomas and cylindromas (Brooke-Spiegler disease) have been linked to chromosome 16q12-q13 {5,722}.
Prognosis and predictive factors Because these are benign neoplasms, no treatment is required, in most cases, if the diagnosis is established with certainty. Because some trichoblastomas may occur, rarely, in association with basal cell (trichoblastic) carcinoma, and because of the difficulty in establishing the diagnosis in superficial biopsies, in some cases, additional biopsy or excision should be considered if there is uncertainty about the diagnosis.
Pilomatricoma
Definition Pilomatricoma is a relatively common benign cutaneous adnexal neoplasm with differentiation towards the matrix and inner sheath of a normal hair follicle as well as hair cortex {28,1169}. ICD-O code 8110/0
Synonyms Pilomatrixoma, calcifying epithelioma of Malherbe, benign calcifying epithelioma Epidemiology Pilomatricoma accounts for up to 0.2% of all routine dermatopathologic specimens
Benign tumours with follicular differentiation 153
Macroscopy Grossly, pilomatricomas occur mostly as lobulated masses with variable amounts of chalky white or yellow keratinous material on their cut surfaces. Foci with bone may be observed. Histopathology There is usually a relatively well-circumscribed, deep dermal or dermal-subcutaneous, cystic neoplasm surrounded by a variable connective tissue stroma {28, 1169}. A spectrum of histopathologic features reflecting mainly different stages of development is observed in individual lesions. Early and well-developed pilomatricomas are characterized by small to large-sized, cystic lesions lined focally by aggregations of basaloid cells (matrical and supramatrical cells) and few squamoid cells and filled centrally with large masses of eosinophilic cornified material (faulty hair matrix) containing shadow (ghost) cells as well as a few keratin filaments. A transition zone of retained nuclei from basaloid cells to eosinophilic cornified material containing shadow cells is focally observed. Basaloid cells exhibit deeply basophilic oval or round nuclei and a variable number of mitotic figures. Inflamed or regressing pilomatricomas are relatively large cystic tumours with prominent areas of shadow cells and foci of basaloid and/or squamoid cells surrounded by a variable, often dense inflammatory infiltrate with histiocytic giant cells, and occasionally siderophages and/or melanophages. Areas of granulation tissue may be present. Occasional lesions dis-
Fig. 3.41 Pilomatricoma. There is a growth component of basolid cells with transition to pilar shadow cells.
in certain centres. The tumour occurs in all age groups {1169}. About 30-50% of cases present in young individuals less than 30 years of age. Previous studies have shown a female predominance. Localization Pilomatricomas favour hair-bearing areas, with the majority of cases arising in the head and neck region as well as upper extremities. Clinical features Patients present with solitary, asymptomatic, slowly growing, cystic or firm nodules measuring 0.5-3 cm in diameter {28,1169,1170}. Lesions are commonly
skin-coloured, but may show a bluishpurple to reddish hue or pigmentation. Unusual presentations include rapidly growing or giant tumours (measuring up to 15 cm in diameter), lesions with overlying striae or anetodermic changes, and multiple tumours. Multiple pilomatricomas are quite rare. They are a marker for myotonic dystrophy, and may rarely be associated with a number of different conditions including Rubinstein-Taybi syndrome, Turner syndrome, Goldenhar syndrome, sternal cleft defects, coagulative defects, and sarcoidosis. Pilomatricoma-like features are an occasional finding in cutaneous cysts removed from patients with Gardner syndrome.
Fig. 3.42 Tricholemmoma. A Exo-endophytic tumour with wart-like silhouette and focal desmoplastic stroma. B Peripheral epithelia are arranged in a palisade. Small central follicular microcyst.
play features of transepidermal elimination of shadow cells (perforating pilomatricoma) or a keratoacanthoma-like pattern. Old pilomatricoma lesions reveal no epithelial components but show irregularly shaped, partially confluent, focally calcified or metaplastically ossified shadow cell areas embedded in a desmoplastic stroma, with little or no inflammatory infiltrate. Extramedullary haematopoiesis has been observed in some regressing and old pilomatricoma lesions. A subset of pilomatricomas, also termed proliferating pilomatricoma, is characterized by the presence of relatively large, solid or solid-cystic basaloid cell areas with small foci of shadow cells {1170}. This variant presents mainly in middle aged and elderly individuals. Matricoma represents another unusual pilomatricoma variant characterized by discrete, small, solid aggregations of basaloid cells with several connections to pre-existing infundibula at different points {28}. Molecular and cytogenetics Derivation of pilomatricomas from the hair matrix has been underlined by recent biochemical studies demonstrating prominent staining of tumour cells with antibodies directed against LEF-1, a marker for hair matrix cells. Mutations in the gene CTNNB1 have been detected in up to 75% of pilomatricomas studied implicating beta-catenin/LEF misregulation as a possible cause of hair matrix cell tumourigenesis {438}. In another study, all 10 pilomatricomas examined were found to display strong bcl-2 immunostaining, a proto-oncogene well known to help in suppressing apoptosis in benign and malignant tumours {712}. This finding supports a role for faulty suppression of apoptosis in the pathogenesis of pilomatricomas. Prognosis and predictive factors Treatment is recommended mainly to avoid a foreign body reaction and inflammation with eventual scarring. Surgical excision is usually curative, but occasional recurrences may be observed. Spontaneous regression has been reported in a few cases. Malignant transformation has only been suspected in a single case of pilomatrical carcinoma {2064}.
Fig. 3.43 Tricholemmoma. A Thick PAS-positive basement membrane. B Focal necrosis within bulbous follicular hyperplasia. Thickened basement membrane. C Desmoplastic stroma with entrapped bizarre epithelial strands (pseudoinvasive interface). D PAS-positive desmoplastic stroma and basement membrane.
Tricholemmoma
Definition Tricholemmoma (TL) is a benign folliculoinfundibular proliferation occurring frequently but not exclusively on the face of adults. Multiple tricholemmomas may be associated with Cowden disease. ICD-O code Tricholemmoma 8102/0 Multiple tricholemmomas 8102/0 Synonyms Trichilemmoma Epidemiology TL is a relatively common cutaneous proliferation that occurs mostly in adults and affects both sexes equally {323}. Multiple TLs, often in conjunction with acral keratoses, palmar pits, and oral fibromas, are a cutaneous marker of Cowden disease (multiple hamartoma and neoplasia syndrome) {322,325,681,2025,2247, 2249-2251}. Localization TL arises on the head and neck, almost exclusively on the face, favouring the centrofacial area. Rarely, TL may occur in naevus sebaceous {410,1979}.
Clinical features Patients usually present with a solitary asymptomatic exophytic centrofacial lesion which is either wart-like with verrucous and keratotic features or dome shaped with a smooth surface. Individual lesions are small, varying in diameter between 3 and 8 mm {28}. Multiple facial TLs are almost invariably associated with Cowden disease {2247,2249-2251}. Histopathology Most cases of TL present as a sharply circumscribed superficial exo-endophytic proliferation with a papillated surface. There is marked parakeratosis, hyperkeratosis, and wedge-shaped hypergranulosis of the infundibula, in conjunction with a collarette of embracing adnexal epithelium {28,323}. TL does not involve the interfollicular epidermis. The dominating histological pattern of TL is that of a bulbous infundibular hyperplasia with tricholemmal differentiation, akin to the outer root sheath of the hair follicle {28}. There are one or more bulbous lobules, always in continuity with the epidermis. These lobules consist of numerous pale and clear isomorphic epithelia, most of which are PAS positive. At the periphery, pale columnar cells are arranged in a palisade, bordered by a prominent PAS-
ICD-O code
8101/0
Epidemiology TF represents a rare hamartoma mostly occurring during adulthood (with a wide range of ages between 11 and 77 years {28}) without sex predilection {887}. Localization TF favours the head and neck region, foremost the face. Most lesions are situated around the nose {887}. Clinical features TF presents as a solitary asymptomatic dome-shaped lesion with a smooth surface and a widely dilated central ostium from which a small tuft of delicate white hairs emerges. Lesions are small, ranging between 0.5 and 1.0 cm in diameter {28}.
Fig. 3.44 Trichofolliculoma. A Note reticulate pattern of vellus follicles in devolution. B Detail. Reticulate epithelial strands, sebaceous lobules and few vellus follicles. C Note sebaceous lobules and dense fibrotic stroma. Vellus follicles in different stages of devolution.
and type IV collagen-positive basement membrane. Central foci of epidermal / infundibular keratinization, occasional small and inconspicuous squamous eddies, and keratinous microcysts in larger lesions are occasional findings {28}. There are no mitoses. Desmoplastic tricholemmoma is a variant of TL characterized by a highly desmoplastic stroma with broad zones of sclerosis and distinctive artifactual clefts. Instead of pushing smooth lobular contours there may be a pseudoinvasive interface akin to pseudocarcinomatous epithelial hyperplasia, simulating carcinomatous growth {1079,2333}. Differential diagnosis Warts, basal cell carcinomas, squamous cell carcinomas, trichoblastomas, seborrhoeic keratoses, and keratosis follicularis inversa may contain areas of tricholemmal differentiation {31,1931}. The tumour of the follicular infundibulum exhibits a plate-like pattern with interconnecting horizontally oriented epithelial strands. Inverted follicular keratosis consists of basaloid and squamous epithelia, associated with large numbers of squamous eddies (i.e. concentric layers of squamous cells in a whorled pattern, sometimes keratinized).
Histogenesis According to strict topographical anatomical criteria, TL arises from the follicular infundibulum and differentiates toward the outer [tricholemmal] root sheath {28}. Its superficial folliculo-infundibular location militates against the classification of TL as a neoplasm of the lower portion of the hair follicle (i.e. the [outer] tricholemmal sheath). However, it is still a matter of debate whether TL is of hamartomatous/neoplastic {318,991,1906,1931} or of viral origin {15,28,31}. The detection of HPV DNA in tricholemmomas by PCR {2688} favours the latter view of TL as a resolving verruca vulgaris with tricholemmal differentiation {15,28, 31}. Prognosis and predictive factors TL is an entirely benign cutaneous neoplasm. Multiple TLs are a hallmark of Cowden disease and should prompt a search for internal malignancy.
Trichofolliculoma
Definition Trichofolliculoma (TF) is a follicularly differentiated hamartoma generally appearing during adult life.
Histopathology The main histological features of TF are reflected by its Caput Medusae pattern {28}: embedded in a highly fibrocytic stroma, large numbers of vellus follicles with upper and lower segments like those of normal follicles radiate from the perimeter of a dilated infundibulum. TF is a symmetrical, well-circumscribed, vertically oriented lesion composed of three components: infundibulo-cystic, follicular, and stromal {28}. The centre of the lesion is occupied by one or more widely dilated infundibulo-cystic structures that are continuous with the epidermis and open to the surface of the skin through an ostium. The cystic lumina may be filled with innumerable corneocytes and vellus hairs. From the epithelial walls of the infundibular cystic spaces smaller infundibula radiate, to which are attached vellus follicles in various numbers. These vellus follicles are not associated with muscles of hair erection or with sebaceous ducts, albeit sebaceous cells arranged as solitary units or in lobules may occur within the lining epithelium of the central infundibulo-cystic structure. The morphology of the individual vellus follicles may vary from normal to strikingly aberrant {28}. Normal vellus follicles may exhibit all stages of the follicular cycle {2106}. The whole lesion is embedded in a cellular connective tissue sheath, which is separated from the adjacent normal dermis by prominent shrinkage clefts. The highly fibrocytic stroma
which surrounds the individual vellus follicle resembles perifollicular sheath {28}. The existence of considerable numbers of Merkel cells in all trichofolliculomas underlines their classification as hamartomas with follicular differentiation {967}. Variants TF is a complex lesion with protean features {28}. Some of these are caused by the evolutionary and devolutionary alteration of the vellus hair follicles in their regular biological cycles {2106}. In this context, folliculo-sebaceous cystic hamartoma {1275,2187} may be interpreted as a TF at its very late stage with nearly complete regression of the transient follicular epithelium, but with concurrent growth and maturation of sebaceous elements {2105}. Sebaceous trichofolliculoma {1846} exhibits distinct sebaceous lobules at its outer circumference, but lacks vellus follicles that radiate from the epithelial lining of the dilated infundibulum. The latter criterion militates against the classification of sebaceous trichofolliculoma as a true TF {28}. Hair follicle naevus is regarded as a TF that was histologically sampled at its periphery {28}. There is a striking predominance of mature vellus follicles and the central infundibular lumen may be quite inconspicuous. Prognosis and predictive factors TF represents an entirely benign cutaneous hamartoma with no reports of tumour progression or aggressive clinical course.
Fig. 3.45 Pilar sheath acanthoma. A The characteristic infundibular and isthmic differentiation is stereotyped. Note the lack of a hair filament or inner root sheath. B The lobule contains red-pink corneocytes, characteristic of the isthmus. C This pilar sheath acanthoma does not have the obvious widened ostium, but it does contain the lobules of isthmic epithelium. D The lobules have a nearly syncytial pattern. E This lobule has clear-cell changes and syncytial, pink cell changes. Note the lack of inner sheath or hair filament. F The small, partly cornified cyst seen here contains no hair filament. Parts of the transient portion of the follicle are rarely seen in pilar sheath acanthoma.
Pilar sheath acanthoma

Definition Pilar sheath acanthoma is a follicular neoplasm differentiated toward the permanent part of the hair follicle, to wit, the infundibulum and the isthmus. [The infundibulum is an extension of epidermis to meet the isthmus, but both function as part of the follicular sheath]. Synonyms Infundibuloisthmicoma Clinical features Pilar sheath acanthomas affect adults of either sex, and are identified usually on the face. They are small, solitary papules up to 5 mm in diameter, with a central 1-
2 mm punctum, lacking hair filaments, and will express corneocytes if squeezed. There are no known associated syndromes and no known genetic abnormalities within the neoplasms {29, 232,473,1570,2212,2402}. Histopathology The classical example consists of a patulous infundibulum that connects with lobules of epithelium differentiated toward both the infundibulum and the isthmus. This differentiation results in blue-gray (infundibular) and pink (isthmic) corneocytes that fill the follicular canal. There can be a minor component of stem or bulb (or both) differentiation in some examples. Consequently there is, as a rule, no evidence of hair filaments in these neoplasms.
Differential diagnosis Pilar sheath acanthoma should be differentiated from dilated pore (Winer), trichofolliculoma, and fibrofolliculoma/trichodiscoma. Dilated pore is an infundibular cyst that has proliferated minimally, but lacks isthmic differentiation. Trichofolliculoma is a hamartoma and contains fully formed vellus hair follicles that radiate around a centrally positioned cyst. Fibrofolliculoma/trichodiscoma is also a hamartoma found characteristically in the Birt-Hogg-Dub syndrome and that contains thin strands of infundibular epithelium connected so that fenestrations of delicate fibrous stroma are found within. Additionally, considerable stroma, lacking epithelium, is often identified (trichodiscoma).
Synonyms Trichodiscoma first was erroneously thought to arise from or to differentiate toward the hair disk (Haarscheibe) and therefore bears this name {1836}. Fibrofolliculoma was often used for perifollicular fibroma in the past. Neurofollicular hamartoma and trichodiscoma are the same {2048}. Mantleoma was used as the overall term for both fibrofolliculoma and trichodiscoma {27}. Epidemiology Fibrofolliculomas/trichodiscomas are rare appendageal tumours, occurring equally in males and females, usually not before the third decade of life. Etiology The etiology of the solitary lesions is unknown. The BHD gene was mapped to 17p11.2 {1256}. Localization The preferred sites of location are the face, neck and chest. Clinical features Fibrofolliculomas and trichodiscomas cannot be distinguished clinically {248}. The onset of the lesions is mostly in the third to fourth decade of life. They are skin coloured, smooth, dome-shaped papules, measuring 2-4 mm in diameter {248}. The lesions are asymptomatic. Histopathology There is a histomorphological continuum between fibrofolliculoma and trichodiscoma. However, most of these presented cases were actually fibrofolliculomas which were merely prepared histologically in an unusual sectioning technique, resulting in misinterpretation as perifollicular fibroma {2107}. Fibrofolliculoma The fibrofolliculoma is composed of similar amounts of epithelial as well as mesenchymal elements. At scanning magnification there are one or several adjacent small, vertically oriented infundibulocystic structures, surrounded by a prominent stroma, which is well demarcated from the surrounding normal reticular dermis by clefts. Anastomosing cords and strands of epithelium arise from the dilated infundibulum. Often, cells with sebaceous differentiation are apparent in these epithelial cords. The surrounding
Fig. 3.46 Histopathology of a typical tumour of the follicular infundibulum, with horizontal proliferation of pale keratinocytes in the papillary dermis. Note the connection with the overlying epidermis.
Prognosis and predictive factors The neoplasm is benign; no treatment is necessary.
Tumour of the follicular infundibulum

Definition Tumour of the follicular infundibulum (TFI) is a benign epithelial neoplasm of follicular origin. Synonym Infundibular tumour. Epidemiology TFI is an uncommon tumour occurring in adults, mainly after the age of 50. In two studies, TFI accounted for less than 10 per 100,000 skin samples. They can be observed on the face of patients with Cowden syndrome or on the surface of naevus sebaceous. Localization and clinical features Solitary TFI is mainly localized on the face and presents as a small fleshcoloured nodule, resembling basal cell carcinoma. Multiple or eruptive TFI present as hundreds of symmetrically distributed hypopigmented geometric macules localized on the face, neck, trunk, or on the periocular area. Sun exposure increases the contrast between normal skin and the tumours. Histopathology TFI is a plate-like horizontal proliferation
of pale keratinocytes, which is localized in the papillary dermis and shows multiple connections with the overlying epidermis or with the infundibulum. The cells are paler and larger than normal keratinocytes and their cytoplasm stains with PAS. The tumour is sharply circumscribed and limited by a dense network of elastic fibres easily demonstrated by orcein staining. Desmoplastic and sebaceous variants have been described {557,1485}. Histogenesis TFI derives from the normal follicular infundibulum. The occurrence of multiple TFI suggests a possible genetic basis, which remains to be established. Prognosis and predictive factors The prognosis is good, except in rare patients with multiple TFI who may develop basal cell carcinomas.
Fibrofolliculoma / trichodiscoma
Definition Fibrofolliculoma and trichodiscoma are different developmental stages in the life of one single benign appendageal hamartomatous tumour, which differentiates towards the mantle of the hair follicle {27}. Fibrofolliculoma represents the early and trichodiscoma the late stage in the development of this lesion {27}. ICD-O code 8391/0
prominent stroma is made up of fine, fibrillary ribbon-like bundles of collagen, often arranged parallel to one another and perpendicular to the epithelial cords. The stroma contains numerous spindled fibrocytes and many venules and capillaries. Elastic fibres are markedly reduced. The stroma is often mucinous, comparable to the stroma of the follicular mantle-region. Trichodiscoma Trichodiscoma is a horizontally oriented dome-shaped tumour composed of more mesenchymal tissue than epithelial elements. A prominent tumour stroma of elliptical shape is seen, possessing the same cellular characteristics as in fibrofolliculoma. In peripheral zones of this prominent stroma, small groups of sebaceous lobules may be found. Mantle-like epithelial structures are uncommon. Plaque-like variants of fibrofolliculomas/ trichodiscomas with confluence of single lesions and a resulting extension up to several cm in diameter have been described {2103}. The differential diagnosis of fibrofolliculoma includes trichofolliculoma at a late stage {2105}. Fatty tissue is a typical finding in late stages of trichofolliculoma but not in fibrofolliculoma. Perifollicular fibroma/fibrous papule is also similar to fibrofolliculoma. However, it is usually devoid of mucin and shows no mantlelike epithelial proliferations {27}. Trichodiscomas have to be differentiated from neurofibromas and cutaneous myxomas {521}. However, the latter tumours lack the sebaceous epithelial component, typical of trichodiscoma. Immunoprofile The epithelial and mesenchymal parts of the lesions show the common reactivities to cytokeratins and vimentin. The tumour stroma is strongly reactive with antibodies to CD34, reflecting its differentiation towards the follicular mantle region. Histogenesis Histologic and immunohistologic data suggest that fibrofolliculoma/trichodiscoma is derived from/differentiated to the mantle region of the hair follicle {27,521}. The mantle region is a specialized epithelial-mesenchymal structure, located at the lower end of the follicular infundibulum {606} and is the source and starting point for the development of the
sebaceous glands {27}. Fibrofolliculoma/ trichodiscoma is considered to be a hamartomatous lesion. Its mesenchymal part may be responsible for the origin and growth of the whole lesion, leading to the distinctive mesenchymal- epithelial proliferation, reminiscent of a deformed mantle region {2103}. The postulated cell of origin therefore might be a specialized dermal dendritic spindle cell, normally situated in the mantle region {521,2103}. Genetic susceptibility Multiple fibrofolliculomas/trichodiscomas are part of the Birt-Hogg-Dub syndrome (BHD), an autosomal inherited syndrome, also affecting the lung and kidney {248,2579}. The BHD gene is located at 17p11.2 {806} and encodes folliculin whose function is unknown. The patients may have multiple, often bilateral renal carcinomas, frequently representing unusual histological subtypes. They also have an increased frequency of spontaneous pneumothoraces. Prognosis and predictive factors Fibrofolliculoma/trichodiscoma is a benign lesion, excised primarily for cosmetic reasons. However, it is an important marker for Birt-Hogg-Dub syndrome and its associated complications.
Tumours with sebaceous differentiation
A. Rtten M.R. Wick O. P. Sangeza C. Wallace
Sebaceous carcinoma
Definition Sebaceous carcinoma (SC) is a cytologically- and/or architecturally- malignant neoplasm demonstrating exclusive sebocytic differentiation. ICD-O code 8410/3
Historical annotation Historically, SCs have been subcategorized into ocular and extraocular subtypes {1510A, 1696A, 1827A, 1856A, 2511A,2609A}, although there is no inherent biological difference between such lesions. Epidemiology SC usually arises in adults, with an average patient age of 62 yrs. and a female predominance, by a factor of roughly 2:1. Tumours of the eyelids are preferentially seen in Asian patients, and also may represent a complication of prior radiotherapy {1067A}. Clinical features All SCs present as painless masses, which can be multifocal. In the ocular adnexae, they may be mistaken clinically for chalazions, blepharitis, cicatricial pemphigoid, or conjunctivitis {642,839, 2542}. In extraocular sites, sebaceous malignancies are commonly confused with basal cell carcinomas and squamous cell carcinomas. Most extraocular SCs are encountered in the skin of the head and neck, followed by the trunk, genitals, and extremities. Rare cases may also be seen in the mouth, salivary glands, lungs, and breasts. Macroscopy SCs are nodules that typically enlarge slowly but may occasionally grow rapidly; some become ulcerated. A minority of individuals with this tumour have the Muir-Torre syndrome {2227}.
Histopathology Sebocytic differentiation, typified by multivesicular and vacuolated clear cytoplasm, is the sine qua non for sebaceous neoplasms including SC. It must be separated from simple cytoplasmic clarity, a microscopic change that is relatively common in cutaneous neoplasms of many other lineages {2294}. SCs are organoid proliferations comprising dermal lobules of variably-atypical polygo-
nal cells, with a fibrovascular stroma that typically lacks desmoplasia. Central portions of the tumour cell nests may be necrotic, yielding a comedo growth pattern. The cells of well-differentiated neoplasms show abundant cytoplasm and oval vesicular nuclei with distinct nucleoli; mitotic figures are variable in number. On the other hand, more poorlydifferentiated SCs show high nuclear-tocytoplasmic ratios, nuclear pleomor-
Fig. 3.47 Sebaceous carcinoma. A Sebaceous carcinoma, represented by a lobular proliferation of atypical epithelioid cells in the dermis. Multivesicular cytoplasmic vesiculation is present. B Extensive in-situ involvement of the surface epithelium is present in this example of sebaceous carcinoma. C Bubbly cytoplasmic vacuolization is apparent in sebaceous carcinoma.
phism, prominent nucleoli, brisk mitotic activity - sometimes with pathologicallyshaped forms - and amphophilic or basophilic cytoplasm. Intracellular vacuoles are sometimes not seen easily in those lesions, and may require the use of special histochemical stains, such as the oil-red-O or Sudan IV methods, to detect them {2540}. The grading of SCs - into grades I through III - is based on growth patterns rather than on their cytological features {1892}. Tumours that are constituted by well-demarcated, roughly equally-sized cellular lobules are graded as I; those with an admixture of well-defined nests with infiltrative profiles or confluent cell groups are grade II lesions; and grade III SCs exhibit highly-invasive growth or a medullary sheet-like pattern. All SCs have the potential for an association with overlying carcinoma in-situ (CIS), or extramammary Paget disease (EPD) of the sebaceous type, or both, in the surface epithelium and in other epidermal appendages (especially pilosebaceous units) {448,1702}. The latter lesions are probably marker lesions that represent a cutaneous field defect, rather than being direct precursors of, or extensions from, underlying SC. This premise has support from occasional cases in which only intraepithelial sebaceous carcinoma is present, in the absence of an invasive component in the dermis {1510}. In pragmatic terms, however, one should always consider the possibility of infiltrative SC whenever EPD or carcinoma in-situ is seen in a superficial biopsy.
Variants Selected microscopic variants of SC deserve special comment because they may engender interpretative confusion with other cutaneous tumours {2540, 2542}. Basaloid SC comprises small cells with scant cytoplasm, and may often show nuclear palisading at the periphery of cellular nests. It commonly manifests a grade III growth pattern, and overtlysebocytic elements are sparse and difficult to identify as such. Squamoid SC shows prominent squamous metaplasia, often with keratin pearl formation; some examples may also demonstrate spindle-cell areas, equating with a sarcomatoid image. Still other examples of SC may demonstrate pseudo-neuroendocrine organoid growth, focally resembling the pattern of carcinoid tumours {1235}. Based on these brief descriptions, one could easily predict that basal cell carcinoma, squamous cell carcinoma, neuroendocrine tumours, epithelial malignancies with potential spindle-cell differentiation, and a variety of clear-cell neoplasms in the skin may enter differential diagnostic consideration in selected cases of SC. Immunoprofile SC shows immunoreactivity for several generic epithelial markers such as pankeratin, epithelial membrane antigen (EMA), CD15, CU18, CA15.3, and Thomsen-Friedenreich antigen {75}. EMA labeling may enhance the cytoplasmic bubbliness of the tumour cells in this neoplasm. That pattern is distinctive, but
it is not observed in all examples of SC. Reactivity for androgen receptor protein and human milk fat globule protein-2 also has been reported in SC {182,2191}. However, it is not yet know whether the latter markers are diagnostically helpful in excluding other clear-cell tumours. Genetic susceptibility Immunoreactivity in SC for various DNAmismatch repair gene products, especially for MSH-2, has been correlated with a relationship to the Muir-Torre complex {1468,1536}. However, virtually no systematic data are available on the detailed genetic profiles of either sporadic or syndromic SC. Prognosis and predicitive factors Both ocular and extraocular SCs have a 30-40% risk for local tumour recurrence, 20-25% for distant metastases, and 1020% for tumour-related mortality {1645}. Some reports appear to support the premise that immunoreactivity for mutant p53 protein at a level of >10%, and for proliferating cell nuclear antigen at a level of >25% may be linked to an adverse outcome {977}. A similar comment may apply to those lesions that overexpress the c-erbB-2/HER-2/neu protein {472,977}.
Sebaceous adenoma
Definition Sebaceous adenoma is a small tumour composed of basaloid cells and fully differentiated sebocytes.
Fig. 3.48 Sebaceous adenoma. A Well circumscribed lobulated sebaceous tumour. Fully differentiated sebocytes predominate and epidermis is replaced by the tumour. B High magnification of the periphery of the lobule.
Tumours with sebaceous differentiation 161
match repair gene defect show a microsatellite instability in a high percentage {1334}. Prognosis and predictive factors Sebaceous adenomas are benign tumours. If the patient has Muir-Torre syndrome, the prognosis depends on the associated internal malignancies.
Sebaceoma
Definition Sebaceoma is a benign, adnexal neoplasm with sebaceous differentiation. It is characterized by multiple, smooth-bordered lobules and cystic spaces composed primarily of immature sebaceous cells admixed with randomly scattered mature sebocytes.
ICD-O code
8410/0
Fig. 3.49 Sebaceoma. A Low power view demonstrating a neoplasm with multiple well-circumscribed nodules of different sizes. B Example of a reticulated sebaceoma. The neoplasm is composed predominantly of uniform basaloid cells distributed in a reticulated pattern. Please note the presence of cells with sebaceous differentiation at the base of the lesion. C Cytologically the basaloid cells are uniform and present between collagen bundles.
Synonyms Sebaceous epithelioma, basal cell epithelioma with sebaceous differentiation, and sebomatricoma. Epidemiology Sebaceomas are rare sebaceous neoplasms that may be associated with the Muir-Torre syndrome {1624,2114}. They typically arise in late adulthood with the mean age of diagnosis being at approximately 70 years of age, but may be seen in early adulthood {2378}. The tumours have a predilection for females. Localization Sebaceomas occur mainly on the face and scalp, with rare cases reported on the trunk {226,636,1710,1749,1922, 2258,2378}. Clinical features Clinically, sebaceomas present as yellow to orange solitary papules on the head and neck {636,2258,2378}. Those lesions associated with the Muir-Torre syndrome may be multiple {347,1624, 2114}. They are slow-growing neoplasms and do not recur after excision {636, 2258,2378}. Histopathology Architecturally sebaceoma is composed of multiple well-circumscribed lobules of various size centred on the dermis. The lobules often contain ducts and cystic
ICD-O code
8410/0
Epidemiology Sebaceous adenomas occur mostly as solitary lesions in persons older than forty years {1993}. Lesions are located usually on sun-damaged skin of the head and neck area. Rarely patients have multiple lesions {2258}, then the possibility of Muir-Torre syndrome should be considered. Clinical features Sebaceous adenomas are relatively small yellowish tumours often covered by a scale or crust {2353}. Histopathology This well-circumscribed tumour is made up of small lobular aggregations of sebocytes with a rim of basaloid cells at the periphery, recapitulating the maturation of sebocytes from the periphery to the centre comparable to normal sebaceous glands {1542}. Lobules are composed of vacuolated fully differentiated sebocytes and these cells predominate markedly over the basaloid sebocytes. Sebaceous adenoma is often connected to the overlying epidermis, and may be covered by a thick plug of keratin and disintegrated
sebocytes. Ductal structures are rare, as are mitotic figures. Sebaceous adenoma has to be differentiated from sebaceous hyperplasia, where the sebaceous lobules are arranged around a central placed follicular infundibulum that is connected to the epidermis. In sebaceous hyperplasia the epidermis may show changes mimicking seborrhoeic keratosis. Sebaceomas are nodular lesions of basaloid undifferentiated sebocytes and only a few small groups of vacuolated sebocytes. There may be morphological overlaps between sebaceous adenoma and sebaceoma. The term sebomatricoma was introduced as an attempt to simplify the nomenclature of the different benign sebaceous adnexal tumours and to summarize them under one name {2003}. Genetics Little is known about the genetics of sebaceous adenoma. Most of the tumours occur as solitary lesions but a few examples of SA are part of the spectrum of different sebaceous tumours in MTS. By immunohistochemistry it is possible to look for a loss of MSH-2, MLH-1 repair proteins. Tumours related to a mis-
areas containing holocrine secretion and only rarely do they connect with the overlying epidermis. A brightly eosinophilic cuticular material lines both the ducts and cysts, similar to what is seen in the normal sebaceous ducts. Cytologically the neoplasm is comprised predominantly of small, uniform basaloid cells with bland nuclear features admixed with haphazardly distributed mature-appearing sebaceous cells. The mature sebaceous cells have abundant vacuolated cytoplasm and ovoid nuclei, which often have a scalloped nuclear membrane. Rare typical mitoses may be seen, however, atypical mitosis and necrosis are not features of sebaceoma. The surrounding stroma is dense, eosinophilic connective tissue. There is no cleft seen between the neoplasm and the stroma, as is the case with basal cell carcinoma. A wide variety of patterns have been described for sebaceoma, sometimes even within the same neoplasm. These include reticulated, cribriform and glandular {634,1710}. There have been reports of a variant with eccrine differentiation, a pigmented variant and a sebaceoma that arose in a seborrhoeic keratosis {226,1749,1922}. Those lesions that arise in Muir-Torre syndrome may have a keratoacanthoma-like architecture {347}. Immunoprofile Immunohistochemistry demonstrates positivity with high-molecular weight keratin. EMA stains most mature sebocytes, and thus will only show positivity of the mature vacuolated sebaceous cells scattered amongst the tumour, while the basaloid cell compartment will be negative {1710}. Several reports have demonstrated loss of heterozygosity as well as microsatellite instability in a marker gene located near hMSH2 in patients with sebaceoma and Muir-Torre syndrome {1332,1536}. By immunohistochemistry it is possible to look for a loss of MSH-2, MLH-1 repair proteins {1334}. Prognosis and predictive factors Sebaceoma is a benign neoplasm that does not recur after treatment or metastasize. It may be a marker of Muir-Torre syndrome, in which case the patient has a high risk of internal malignancies.
Cystic sebaceous tumour

Definition Cystic sebaceous tumour is a large distinctive tumour with is almost always associated with Muir-Torre syndrome (MTS) {1999}. ICD-O code 8410/0
Epidemiology Cystic sebaceous tumours occur nearly exclusively in MTS, which is a phenotypical variant of the hereditary non polyposis colon cancer syndrome (HNPCC). MTS is inherited in an autosomal-dominant fashion and is caused by genetic alterations within the DNA mismatch repair system. Patients often have a family history of malignancies and most are affected with a variety of internal malignancies such as colon cancer, urothelial cancer, endometrial cancer and others. MTS patients develop a broad spectrum of different sebaceous skin tumours, which may be difficult to classify {347, 1624}, and keratoacanthomas. Among the sebaceous tumours, CSTs are unique because they serve as diagnostic markers for the syndrome. MTS has a male preponderance and is clinically diagnosed mostly in adults older than 40 years. Localization The upper trunk is the most common location. Clinical features CSTs are usually solitary, but rarely can be multiple. They resemble hair follicle cysts and present as dermal nodules. In patients diagnosed with internal malignancies CST is often excised in order to rule out a metastatic skin lesion. Histopathology CST are large, well circumscribed dermal tumours which may connect to the upper dermis, and usually extend into the subcutis. The outer surface of the neoplasm may be obscured in cases with an accompanying granulomatous inflammation due to the ruptured cyst wall. Well-differentiated CST show a cystic growth pattern with a small line of basaloid undifferentiated sebaceous matrix cells at the periphery and a broad
zone of fully differentiated vacuolated sebocytes towards the centre of the cystic tumour. Well-differentiated CST do not show cytological atypia, and have only few mitoses. Ductal structures may be seen in the cyst wall. Proliferation of tumour cells produces infoldings of the cyst wall in some CST. The more solid variants are predominantly composed of undifferentiated sebaceous cells with mitotic figures and variable cytologic atypia. Genetics Germline mutations of the DNA mismatch repair genes are responsible for MTS. In the vast majority of cases the associated tumours show a complete loss of the corresponding mismatch repair protein (MSH2 or MLH1). This can be demonstrated immunohistochemically by antibodies directed against MSH2 and MLH1 protein {1469,1536,2227}. A loss of the nuclear staining for one of these antibodies within the tumour cells accompanied by a positive staining of nuclei in the surrounding tissue strongly suggests loss of the corresponding DNA mismatch repair protein. Typically, these tumours show high microsatellite instability {1332, 1469, 1999}. Prognosis and predictive factors Some authors interpret cystic sebaceous adenoma as a variant of sebaceous carcinoma {1733}. So far there is no clinical evidence that these tumours in any case represent malignant sebaceous tumours {872,1624,1999}. Because of these conflicting views, complete excision is recommended. The prognosis in MTS is determined by the nature of the associated internal malignancies. In most cases CST develops after the first internal malignancy, but in up to 25% of cases they represent the first clinical sign of MTS. Even in a patient with a solitary CST who does not fulfil the clinical criteria for MTS, a molecular genetic analysis may show a germline mutation in a mismatch repair gene {1333}. Because of the specific marker function of CST it is possible to detect patients and families with an inherited DNA mismatch repair defect predisposing to various types of internal cancer.
Tumours with sebaceous differentiation 163

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CHAPTER 3

WHO histological classification of appendageal tumours

8110/3 8103/1 8100/0 8110/0 8102/0 8102/0 8101/0 8391/0

8404/0 8407/0 8409/0 8392/0 8402/0 8403/0 8200/0

8410/3 8410/0 8410/0 8410/0

TNM classification of skin appendageal carcinomas

122 Appendageal tumours

Appendageal skin tumours: Introduction

124 Appendageal tumours

Malignant tumours with apocrine and eccrine differentiation

L. Requena H. Kutzner M. A. Hurt D. J. Santa Cruz A.H. Mehregan

Y. M. Mengesha S. Kohler Z B. Argenyi J. McNiff P. Rudolph O. P. Sangeza

Microcystic adnexal carcinoma

Malignant tumours with apocrine and eccrine differentiation 125

126 Appendageal tumours

Malignant tumours with apocrine and eccrine differentiation 127

128 Appendageal tumours

Malignant tumours with apocrine and eccrine differentiation 129

130 Appendageal tumours

Malignant tumours with apocrine and eccrine differentiation 131

132 Appendageal tumours

Digital papillary carcinoma

Malignant tumours with apocrine and eccrine differentiation 133

Adenoid cystic carcinoma

134 Appendageal tumours

Malignant tumours with apocrine and eccrine differentiation 135

Paget disease and extramammary Paget disease

136 Appendageal tumours

Malignant tumours with apocrine and eccrine differentia 137

138 Appendageal tumours

Benign tumours with apocrine and eccrine differentiation

J. McNiff T.H. McCalmont L. Requena O. P. Sangeza

C. Vassallo R. Rosso G. Borroni E.J. Glusac R.O. Pichardo

Benign tumours with aprocine and eccrine differentiation 139

140 Appendageal tumours

Benign tumours with aprocine and eccrine differentiation 141

142 Appendageal tumours

Localization Most spiradenomas appear on the face

Benign tumours with apocrine and eccrine differentiation 143

144 Appendageal tumours

Tubular and tubular papillary adenoma

Benign tumours with apocrine and eccrine differentiation 145

146 Appendageal tumours

Mixed tumour (chondroid syringoma)

Benign tumours with apocrine and eccrine differentiation 147

148 Appendageal tumours

Malignant tumours with follicular differentiation

Malignant tumours with follicular differentiation 149

evidenced by involvement of regional lymph nodes, lungs and/or bone.

Proliferating tricholemmal tumour

150 Appendageal tumours

Malignant tumours with follicular differentiation 151

Benign tumours with follicular differentiation

M. A. Hurt S. Kaddu H. Kutzner

B. Cribier T. Schulz W. Hartschuh

152 Appendageal tumours

Benign tumours with follicular differentiation 153

154 Appendageal tumours

Benign tumours with follicular differentiation 155

156 Appendageal tumours

Pilar sheath acanthoma

Benign tumours with follicular differentiation 157